WO2016072875A1 - Neuromodulation device - Google Patents

Abstract

The invention refers to a device for inhibiting the neural activity of a carotid sinus nerve (CSN) or carotid body of a subject, the device comprising: one or more transducers configured to apply a signal to the CSN or associated carotid body of the subject, optionally at least two such transducers; and a controller coupled to the one or more transducers, the controller controlling the signal to be applied by the one or more transducers, such that the signal inhibits the neural activity of the CSN or carotid body to produce a physiological response in the subject, wherein the physiological response is one or more of the group consisting of: an increase in insulin sensitivity in the subject, an increase in glucose tolerance in the subject, a decrease in (fasting) plasma glucose concentration in the subject, a reduction in subcutaneous fat content in the subject, and a reduction in obesity in the subject.

Description

DEStRtPTiGN rN£UROiMODOtATiOf¾ DEViCe" his invention relates to ®edicai devices and, m s particularly to medical devices ha deliver nenromodnla ihg therapy. ACKGROUND

The rapid increase in_, prevalence of ifsetaboiic disorders such as type 2 i«fcst¾s SiSil i i s iT2P, or T2DK) , obesity, im a red ¾!i*cps« to!er-anKS (whe e patients ¾<S to develop ? DK it left untreated) constitutes a- severe uhiset medical need. Currently available treatments for these disorders are insuff icient to control the disease in a significan nusaber of patients, and of en p od ce unwanted side effects.

The carotid bodies (CH) are peripheral ehe-aoreceptor that s nse c nges in arterial blood , CC½ and »H levels. Hypoxia, hypercapriia and acidosis are known to accivaca the CB. Upon, sensing changes, the CB modulates the n ural ac ivi y (i.e. the action potential pattern and f equ ncy^'s in their sensory perve, tha carotid sin s nerve iCSJi! , CSii activity is interpreted by the elements of the brain stem that control efferent reflexes including normalisation of blood gases v i a hyperventilation, and the regulation of blood pressure and cardiac perforrnanee via sympathetic n.ervows system {SU activation. Consistent with this notion, CS de~ af f.erentatioo through carotid sinus erv denerv& ion reduces the overactive sympathetic ac ivity in spontaneously hypertensive rats !MeSryde e ai, i_*af ^'Caimmx . 2013; -icdhl&Si ,

Recently, the carotid foody have .been implicated in the control of energy omeost sis and regulation of whole body insulin sensitivity <Riherio ef al. {2015} Iliabefes. 62:: 2§ s-iS_:i Lirtiberg Med HypaiMs&s, 2 14 dun; S.2 ΐ 63 ; ?30 - S3. Sifcerio et ai. ( supra) dsmoiS ate that healthy animals fed high fat or high sugar diet develop insulin resistance and hypertension:, u tha if healthy rats un ergo carotid sinus nerve iCSiSf) resection prior to; beginning th diet, the velopment * insulin resistance and hypertension is prevented. However these procedures, w e perform d on otherwise healthy animal that do not carry any of the associated symptoms or pathologies of metabolic disorders k own to affec the w abo ic system and perpetuate disease. So data are available from anit&sis. more representative of an active disease state.

SUMMARY

Usj.no anxoai models representative of both established type 2 diabetes and developing type 2 diabetes ί "prediabetes* ; , each characterised by insmiin resistance and an impai ed response to glucose., it is demonstrated herein that modulation o neural activit in the CSM can treat conditions associated with impaired glucose control. In particular, in rats exhibiting a isease state comparable to type 2 diabetes as well as in those exhibiting a disease state cosaparafola to prediabetes, modulating CSS^' neural activity restores insulin sensitivity, and also reduces the rate of weight gain and fat ac assol ion iFigures -? for T2D and Table 1 for prediabetes; . In the model of T2D, inhibiting Cs¾ neural ac ivity impro es glucose tol rance and insulin sensitivity back rds; no;:r.u I levels {Figures 8-10 and Figures 20 and 21) , These effects in turn will, have beneficial etfaccs on other conditions associated wi h impaired cont ol of glucose and responses to insulin,, as well as chose conditions associated with increased weight and fat levels, for example obesity and hypertension.

It is further demonstrated herein that in animals in a prediabetic state, the neural activity in: the GSM is notably different to the neural activity in healthy s ivels both at. baseline and upon sensory changes, particularly the frequency and atiipiitude of aggregate action potentials ( ig re 11} . This indicates that a type 2 diabetes- like disease state is closely associated wit a change in neural activity in the SK. This abnormal neural activity associated with the disease state can therefore be Ksoduiated in orde to provide an effective treatment fo the conditions associated with imp i e glucose control and/or insulin resistance. Further, abnormal neural activity ca be a measure of: the disease state and may be used in closed loo to control the modulation - for exam le, detection of abnormal neural activity- in the OSN cap: indicate a disease state, and thereby decerKvine the type and level of m dalation of QSH neural activity to treat that disease state. Modulation of the :henral activity will provide a subtle and versatile isode of treatoebt without necessarily re¾uiring remov l of the €3 . For: example, it will allow the titration of treatment in response to disease progression and treatraent response. The mcxiulation could also achieve a therapeutic effec Whilst -a:;^;? ·.: ; ;v: ng function for other physiological: aspects: of the C.'VJ and carotid body, such as the ability to detect changes rn blood gases and thereby ensuring an adequate physiological response to .exercis , It is clear that adversely affec ing such aspects is no desired in an effective treatment paradigm of metabolic disorders ,

Therefore, in a first aspect is provided a device for inhibiting the neural activit o! a carotid Sinus nerve (CSS? or carotid body of a subject, the do i cu comprising one or m e transducers configured to apply a signal to the CSJJ or associated carotid body of the subject, optionally at least tw such transducers; and a controller coupled to the one or mo e transducers, th controller controlling the signal to be applied by the one or more transducers, such that the signal inhibits the neural activity of the Sii o carotid body o produce & physiological response in the subject, wherein the physiological response is one or more of the group consisting of: an increase in insulin sensitivity in the subject, an increase in glucose tolerance in the subject, decrease in {fasting-; plas∞s glucose concentration in the. subject,, a reduction in subcutaneous fat content in the subject., and a reduction in obesit in the subject.

In anothe aspect is provided method of treating a condition associated with impaired glucose control in: a subject cossprising ifaplanting in the subject a device according to the first aspect, positioning at least one transducer of the apparatus in signalling contact with a CSiT or carotid, body of the subject and activating_: the apparatus ,

in another aspect i provided a method of inhibiting neural signalling in the CSH of a subject comprising implanting: in the subject a device according to the first aspect, positioning at least one transducer of the apparatus in signalling contact with a CSS or carotid foody of the subject, and activating the apparatus,

in a further aspect is provided a method of treating a condition associated wit issipaired glucose control in a subject, the method comprising applying a signal to a part or ail of a carotid sinus :nerve iCS ) and/or a carotid body of said subject to inhibit the neural activit of a CSS in the subjec .

In a further aspect is provided a neurorKoduiatory electrical wave orm for use in treating insulin resistance in a subject, wherein: the a efo m is a kiioherc_K alternating curran {AC} waveform havrng a frequency or 1 to SO KHs, such that, when a pli d to a carotid sinus ne ve (CSS} of the subject, ·: hi? wavef:or» inhibits neural signalling in r ho CSi?,

X» a further aspics is ovided nse of a ne romodulators, device for treating a condition associated w th impaired glucose control in a subject s ch as insulin resistance, by iaoduXating afferent ne ra^'i activity in a carotid sinus ser e of the subj ect .

SOm&r OF THE smm

Figure 1; Example irsxilameBtatioria of device including Pas r taors neuroffiodelation .devices for car ying o;.u: the invention.

Effect of ivperca oric diet ingestion (High -fat (HP) * High suc ose ■CBSu),) during 25 weeks diet K insulin sensitivity as used in the type 11 diabetic rat .«sosfel, deterssine fey the insulin t lerance test, e press as the constant rate for .glucos disappearance {K_m] Oneway J¾HOVA with Eiintietfc's erasIti.plev comparison test . *psO..Q¾, ** .Q..iil, 0O.J. vs values in anireais at 0 weeks of diet. Da a represent means t sm.

Effect of chronic parotid sinus nerve {CS ; bilateral denervation on insulin sensitivity determined toy the insuli tole ance test, ex ressed as the constant rate for glucose disappearance >_.K.K-_f> . C^'SN resection was performed after 1* weeks of HP*BSu diet (type 11 diabetic tat model}. One-way h with DuPpett's multiple comparison test. *·**ρ«β. >? , vs values in animals at Cj weeks of siiet. M 0 , 001 , ys values in anissals at 14 w ks of diet (before Css resectioni . Data represent .means + SEN.

Effect o£ carotid sinus nerve tCSK denervation on fasting olasisi glucose (left. panel s; and insulin sensitivity (right panels!^' determined by the insulin toieraae test, eocpreesed ass the constant rate for oiueose disappearance (£½.·} in contro rats {¾) an high-fat (HF! diet (prediahe ic) rats S5. ¾hlte bars represent values of fasting plasma glucose and insulin sensitivity in control animal without (CSS) denervation. Colour :bars represent values of plasm glucose and insulin sensitivity n rats before and after CSfcf denervation. Rats were^, submitted to 3 weeks of HP diet, dshervated at the ¾eeh and ^m intai ed during w re 3 weeks under the respective diets,

Figure S; Effect of hypercalaric diet ingestion (High-fat (HP? ■?- High sucrose

(HSu)) during 25 weeks diet on weight gam, as used in the type i diabetic rat tsodeX . Data represent means SStt .

Figure St eet of chronic carotid sinus nerve CCS?!} bilateral denervation on body- weight increment between 0-14 weeks and between 1 -2¾ weeks in control animals and in anifnais submitted to hyperealorie diets (High- fat <HF; * high sucrose (HSui } , OSS resection was perforraed af er l¾ weeks of BF-<-HSu diet. Data represent means e S t4.

Fioure 7; Effect of bilateral carotid sinus nerve denervation en (A) total, (¾s

subcutaneous and ICS visceral fat i« animal model of type II diabetes Kistar rats submitted, t 14 and 23 seeks of H *Hsu diet, with bilateral CSK denervation at 14 weeks i . Pat® represent means _± ^■ s^~ .

Figure 3 > Effect of hyperealorie diet ingestion (High-fat PHP} Hig sucrose iHSoi j during 25 weeks on fasting plasma glucose. One -way AM A with Dunnett multiple comparison test. *^¾:p;0,Sl, ***ρ<ί.001 comparing ·.··.:>.I with animals- at 0 weeks of diet . Da a are presented as means * ■SS .

Figure ¾; Effect of chronic carot d sinus nerve iCSh/} bilateral denervation on fasting lssiiia glupose lis^' hypereata i a CKigh- fat (MF) * High su ose !HSi- > animals. CSS resect on was erformed afte |4 weeks of KF+HSu diet. One-way ANOVa with- Duanett'® sauitipis comparison test, **p<0 ,0i vs values in animals before iii.i fating RF+HSti diet, represent rseari.s * s¾ .

Figu e 10: ¾; Oral glucose tolerance in an animal model at typo IX diabetes iSistar rats submitted to 14 and 25 weeks of KF-Hsu diet5 , 8 ; Effect o bilateral carotid sinus nerve denervation at 14 weeks on glucose coisraiice in animal model of type II diabetes {Si star rats submitted to 14 and 2S weeks of HF-Hsu diet, with bilateral CSS? dene va ion at 14 weeks (14 week, readings taken, prio to denervation}!, igu e II; Iteprepeata ive (of S animalsj recordings of carotid sinus- nerve activity in basal condi ions and evoked by hypoxia, in an anisal model of prediabetes {rat fed HF diet for 3 weeks) and in a control rat. &} and S} : recordings of CS cfteffiosensory activity in basal conditions arid evoked by 0%0_S in a H? rat ia nd control rat (Bt ; €· and Di - recordings of CSN cheimss^'ens ry activity iri basal conditions and evoked by S%C½ in a H? (AJ and control (&) rat.

Figure Fifsct of bilateral SA) and unilateral (BJ carotid sinus, nerve (CSN;

resection on insulin sensitivity in an airisj&l model of prediabetes v istar rats submitted to S wesks of HF diet, with bilateral CSN denervation at 3 weeks) . Insulin sensitivity was assessed, h ough- an insulin tolerance test U^'TT) and expressad by the constant of ITT ! j-_f-_fj ; be£or®, one, tw and 3 weeks after CSK resection. CSM resection was performed after 3 weeks of R diet,

Frgure 11; Frocsss flow fo tenrinai studies of bilateral CSH blocking, and process for determining efficacious blocking parameter:? .

Figure 14: &esponses through time of cardiorespiratory function to hypoxia with and withou Hi?AC nerve conduction block

Figure 15: A. Example raw data traces of EMS and EGG. s Onset responses due to

K &C. C. Quantitative respirator rate change to hypoxia with and without KFAC.

Figure 16: Stratifica ion of heart and breathing rate changes induced by KFAC blocks under normoxi .

Figure v? s Data traces of EMG and ECS 20 wdnufces and 1 week post cessation of continuous bilateral carotid sinus nerve block S0H2, ^' 2mk stimulus. Figure 1&; Descriptio of study flow for surgical implantation an recovery in disease model, to valuate insulin and glucos tolerance

Figure 19: Electrode functional impedance measu ements at 10 days implantation show that the iwpXants are appropriate and stable; both acutely and at 10. days post implantation. Results are shown on a logarithmic y-axia Figure > : K--.- o animals from e asss i ) and active intervention (8! groups.

*p 0^,SS, **p<O.0I, for comparison with before diet baseline; ;ip<0.oS_:, for ooiftperise between 13 w eks of diet and ? days afte blocking igure 21; OGXT of animals in s am and active in e ven ion groups. A shows OGTT between the shat; group and the intervention group. B; {blocks and C (share) sh w OGTT for each group at each stage of the procedure. *p 0.05 , **p 0.01, »**p<0.0Ql for ceespariiscn wi h before diet baseline: ;ΙΗρ<0.δ , ftp<G.O01 for comparison between. 13 weeks of: dist^¬ end 7 days af er blocking

The tctii:s as used herein are giver their conventional definition in the art as^; understood by the skilled pe son, unless otherwise defined!, below, In the ease ot an irttdrisiH tenc or doubt, th definition, as provided herein should take precedence .

As used herein,, application ot a signal may equate to the; transfer of. energy in a suitable form to. carry out the intended effect of the signal. That is, application of a signal to a carotid eirsus nerve or carotid body way e¾uat« to the tr ns e of energy to (cr from) the carotid Sinus nexve or carotid body (as appropriate) to carry out the intended effect. For example, the energy transferred fsa .tee electrical, rwschasical (including acoustic, each as ultrasound* , electromagnetic ■■^■■^■■ optical!,; magnetic or erm l energy. It is poped that application of a signal as used herein does not include a pharmaceutical intervention.

As used herein, a " ext -destructive signal" is a signal as defined ftfoovs that, when applied, dos not irreversibly: datsage the underlying neural signal conduction ability of the nerve. That is, application of a non-destructive signal roaiatains the at:, i ivy of the CSP (or tibres thereof, or other nerve tissue to which the signal is applied) to conduct action potentials whan application of the signal ceases, even it that conduc ion is in practice inhibited, or blocked as a resul of application of th nor - destrnet ive: signal.

As used herein, an "im aired glucose control" is taken to mean, an inability to osintain blood glucose le els at a normal level (i.e, within normal Imits for a healthy individual! . As will be appreciated by the skilled person, this will vary Passed on the type of subjec and can be determined by a number of me hods well known in the art, for example a glucose tolerance test (G T! . For example, in humans undergoing an oral glucose tolerance test, a glucose level at 2 hours of less than or equal to · 3 msol h is considered normal, A glucose level at 2^: hours of more than ? . a ■••«(Ol7h is indicative: of: impaired glucose control.

As used herein., "insjulin resistance" is given its normal ce sing in he art - i.e. in su ject or patient exhibiting insulin resistance, the physiological response to insulin in the subject or patient is reiraetoxy, such that a higher level of i sul n is required in order to control blood glucose levels, compared to the .uasn!vn level required i a healthy individual. Insulin sensitivity is used herein ass the reciprocal to insulin, resistance - that is, an increase in insulin sensitivity equates to a decrease in insulin resistance, ana vice versa, insulin resistance ma be determined using any method known in the art, for example a GTT, a hyperinsulinae«ic clamp or an insulin suppression test,

Conditions associated with impaired glucose control include those conditions thought to cause the im airmen (for example insulin resistance, obesity, metabolic syndrome, yp-» I diabetes. Hepatitis C infection, acro^megaly} and conditions xesiuitxng from the impairment (for exam le obesity, sleep apnoea syndrome, dysicpidaemia, hypertension. Type 11 diabetes; . It will foe appreciated that o^e conditions can fee both a cause of and caused by impaired glucose cont ol. Other conditions associated with impaired with glucose control would be appreciated by tbe skilled person. it will also e appreciated cha these nditi ns may also be sssocx-sted with insulin resistance.

As used berein* the carotid sinus^' K«rv¾ iCSS ! is taken to m«aa she afferent fcxaxsch of the glossopharyngeal nerve carrying neural signals from the carotid body to the brain, Ic includes both the c e oreceptor branch and the haroreceptor branch of the CStf, as well as the trunk of the nerve that carries the nerve f bres from the two a£ote;teu ioned branche (the carotid sinus nerve is also ^'fc¾ewm as the nerve of ferine or Hsri.ng ' s nerve; .

As used herein, "neural activity" of a ne e is oaken to mean the signalling activity of the nerve, for example the amplitude, frequency and/or pattern of action potentials in the nerve. The texs "pattern", as sed herein in. the context of action oten i ls in the nerve, is intended to include one o more of; local field potential isd _t compound action, potential s} , aggregate action potential ί ?! , and also magnitudes , frequencies, areas under the curve an4 other patterns of ction potentials in the nerve or sub-groups Se.g,. fascicules) of n urons therein.

Modulatio of neural activity, as used herein, is taken to mean that the signalling activity of the nerve is altered from the baseline neural activity - that is, the signalling activity ot the nerve in the subject prior to any intervention. Such modulatio m inhibit, block, or otherwise change the neural activity compared to baseline activity.

Where the modulation of neural activity is inhibition of neural activity, such inh:i.bit ton may be partial inhibition. Partial inhibition may be such that the total signalling activity of the whole nerve is partially reduced, or that the total signalling activity of a subset of nerve fibres of the nerve is fully reduced ⁽i.e. there is no neural activity i that subse of fibres of the bervei , or that the total signalling of a subset of nerve fibres of the nerve is partially reduced compared to baseline neural activit in that subset of fibres of the nerve, Where the modulation of neural activit is inhibition of neural activity, this also esco:»passes full inhibition of neural activit in the nerve - tha is, there is no neural activity in the whole nerve.

in some cases, the inhibition of neural activity ma be a block of neural activity, where modulation of neural activity is a block on neural activity, such blocking s¾v be a partial block, for example a reduction in neural activity of S%, 10%, 3.5% _s SOI, 30%, 35%, 48%, 45%, 40%.. 50%, S0%, 70%,, S0%, < i% sr Bi, or blocking of neural activity in a subset of nerve fibres Of the nerve. Alternatively, such blocking m y be a full block - i.e. blocking o neural activity in. the whole nerve, A block on neural activity is understood to he blocking neural activity from continuing past the point of the block. That is, when the block is applied., action potentials !tsy travbl along the nerve or subset of nerve fibres to the point of the block, but not beyond the point of the block.

Modulation of neural activity stay also be an alteration in th pattern of actios potentials. Xt will be appreciated that the pattern of action potentials can be modulated without necessa ily changing th overall frequency or ampli ude. For example, modulation of the neural activity may be such that the pattern of action potentials is altered to more closely resemble a health state rather than a disease state:.

modulation of neural activity may comp is ; altering th neural activity in various Other ways, for xample increasing or inhibiting a particula part of the neural activit and/or s imniating w elements of activity, for example in particular intervals of tbsse, in particular frequency bands, according o particular patterns and so forth. Such altering of neural activity may for example represent both increases and/or decreases with respect to the baseline activity. Modulation of the neural activity say fee empora y. As used herein, "tempora y" is ased interchangeably with "reversible" , each bein ts¾s« to raean that the modulated neural ac ivity (whether that i« an in ibi on, black or .other modulation ol neural activity or chaise in pattern versus baseline activity) s; not permanent. That is, upon cessation of the signal, neural activity in the nerve re ur s subst ntially towards baseline neural activity within 1-δ& seconds, o a hin 1-60 minutes* or within ; · 24 hours, optionaliy 1 ·· U hoars. Optionally i -S hours, optionally i-4 hoars., optionally .1-2 hoars, or within 1--7 d s; . optionally -4 days, optionally ^"1- 2 days,- in some: instances of tem orary modulation, the neural activity returns substant rally fsiiy to baseline .neural activity.- That is, he acuta; activity following cessation of tha signal is substantially the same as the neural activity prior to the signal eing applied - i.e, prior to modul ion,

luidulacibn of the neu al activity :¾ay be persistent. As used herein, "persistent" is taken to mean that the modulated neural activity (whether that is an inhibition, block or othsr modulation of neural activit o change in pattern v sus baseline activity? has a prolonged effect. That is, upon cessation of the signal, neural activity in the nerve remains substantially the same as when tha signal was being applied - i.e. the neural activity daring and following moehaiacion is subs antially Modulation of the neural activity ma toe corrective. As used herein, "corrective" is taken to rseaa that the modulated neural activity (whether that is an inhibition, block or ot e raodulation of neural activity or change in. pattern versus baseline activity} alters the neural activity towards the pattern of :u?aural activity in a healthy individual. That is, upon cessation, of the signal, neural activity in the nerve more closely ressetsbles the pattern of action potentials in the CSii observed in a healthy subject than prior to modulation, preferably substan ially tally reset-hies the pattern of action potentials in the CSS observed in a healthy subject.. Such corrective modulation caused by the signal can be any inoculation as defined herein, for example, application of. the signal may result in a block on neural activity, and upon cessation of the signal, the pattens of action potentials in tha nerve resembles the pattern of action potentials observed in a healthy subject. By way ©£ further example, applica ion of the signal may result in modula ion such that the neural activity resetnbies the pattern of action potentials observed in healthy subject, and upon cessation of the signal, the pattern of action potentials in the nerve egains the patter of action potentials observed in a hea11hy sabject ,

As usee herein, an " m rovement in a measurable physiological parameter" is taken to mean that for any given ohysioiogica! parameter, an issprovement is a change in the value of that pa meter in the subject towards the normal value or normal range fox- that value - i.e. towards the expected value in a healthy individual,

?«r an example, in a subject having a condition associated with impaired glucose control, or having insulin resistance, a improvemen in a measurable parameter may be; a: reduction in sympathetic tone, an increase in insulin sensitivity, an incre se: in glucose tolerance, a reduction in total fat mass, a redaction in visceral fat mass, a reduction in subcutaneous fat mass,, reduction in plasma catecholamines, redaction in urinary me a ephrines, and a reduction in glycated haemoglobin Hb&!c; , a reduction in circuiatirig triglycerides, assuming the subject i exhibiting abnormal values for the respective caramel ex .

The physiological effect may be temporary. That is, upon cassation of the signal, the rtaasurad physiological parameter in which an. improvement was induced by the signal returns substantially towards baseline neural activity within i~S0 seconds, or within .1-60 minutes, or within _~¾4 hours, optionall 1-12 hours, optionally i-e hoars, optionali i~¾ hours,, optionaliy · 2 hours, or within 1-? days, optionally 1-4 days, optionally 1-2 days, . In some instances, the. physiological paramete returns substantially fully to baseline neural activity. That is, the value of the physiological parameter foll_.ow.ing cassatio-i of; the sign l is substantially the same as the v lue for the p ys ological parameter prior to the signal being applied -· .ij. prior to modulation.

¾e physiological effect w y be persistent. That is, upon cessation of the: signal, th« value of the measure&bie physiological parameter re^gai s substantially e satse as; whan the signal was beix;g applied - i.e. the value for the physiological parameter _.during and following modulation is sub tantially the same

che physiological effect may be corrective. That is, upon cessation or the signal, the v lue of the measuresbls physiological parameter pore closely resembles the value tor that parameter observed in a healthy subject than prior to modulation, preferably subs an ially fully resembles the value for that parameter obse ved in a hea1 thy subjact .

As usee! herein, a physiological parameter is not affected by modulation of the neural activity if the parameter does not change as a result of the modulation from the average value of that parameter exhibited by the subject or subject when ho ix;tarvex:tion has beer; performed - i.e. it does not depart fr m the baseline value for that parameter.

The skilled person will appreciate that the baseline for any neural activity or physiological parameter in an individual need not be a fixed or specific value, but rather can fluctuate within a normal range or may be an a erage value with assxxciated erro and confidence intervals. Suitable methods for determining baseline values would be well known to the skilled person.

As -us-ad herein, a measurable physiological parameter is detected in a subject when the value for that parameter exhibited by the subject at the time of detection is decermined. detector is any element able to make such a determination.

e redefined threshold value" for a physiological parameter is tne n;i¾imu;a her ■■;aximu«;5 value for that parameter that must be exhibited by a subject or subject before the specified intervention is applied, For any given parameter, the threshold value may be defined as a value indicative of a pathological state or a disease state fe.g< sympathetic tone {neural., h odynamic ¾e.-g. heart rate, blood pressure, heart rate variability} or circulating plasma/urine .bio-¾arkers) greater than a threshold sympathetic tone, or greater than a sympathetic tone in a health individual, blood insulin levels greater than health levels. CSS signalling exhibiting a certain activity level or pattern} . Alternatively, the threshold value m be defined as a value indicative of a physiological state of the subject i hat the subject is, for example, asleep, post - prandial , or exercising j . Appropriate values for any given pa siaeter would be stroply determined by tha skilled person ;ior example, with reference to medical standards of practice} .

Such a threshold value for a given physiological paramete is exceeded if the value exhibited by the subject is beyond the threshold value - that is, the_: exhibited value i a greater departure from the normal or healthy value fo that parameter than the predefined threshold value..

A "neu omodulati n device" or ^¾ne roHtodulation apparatus" as used herein is a device configured to moduiafe the neural activity of a nerve, Keuromodula.t ion devices or apparatuses as described herein can be comprised of one or more parts. The ueuromodui ion devices or apparatuses comprise at leas one transducer eapabie of effectivel applying a signal to a nerve. In those embodiments in which the neuromoduiation device is at least partially implanted in the .subject, the elements of the device that are to be implanted is the subject ar constructed such that they are suitable for such implantation, Such suitable constructions would be well known to the skilled person. Va ious; exemplary fully implantable neorosoduiativOft devices are curren ly available, such as the vagus nerve s ipulat r of Sefc*oi»fc Kedical, in clinical tiavel.oprrient for the ^'treet!BanS of .r e-utaatoid art&eicis i Arteritis & Rheumati sm, Vs.. se &4, fio. 10 .('Supp ement) _< page S.ISS (Abstract No, $$1} , Oc ober 2013. " ilot Staciy rr Stimulation of the Choi ;;u:u- ;c A:>^;: i^■ .; nf i a^;;;»a very th ay wi tii : iu. c»h :x: Vnxus ,<¾·>· v scimtl_.it im D v e .1» meivros vi th R &imavpid Artbri cis^!i , Frieda A. Koopstan ef ai) .. ana the T TSRSTIM* device ^; ed rosv:c, inc.}, ¾ icily raipiantable device utilised for sacral nerve ^duration in. the t eatmen i overact ! vo bladder ,

Suitable neuromodulation devices can be fabricated with characte istics as descri ed herein, fo example Cor implanta ion within t e nerve ie.g, intra!ascicnlarly| , tor par tially Or wholly surrounding the :;«χ νε (e-g. a cut^';:^' i.nherfa.se: with the nerve} .

As osed herein, "isspXaBted* is taken to mean positioned within the sub ee t ' s body , Partial implanta ion me ns that only part of the device is; implanted ^■· i.o, only part of the devic is positioned within the s b ec 's body, with other sievents of the device ex e nal to the subject's body. For example, the transducer and controller of the device taay be wholly ίcaplata:ed within the subject, and an input element may be external to the subject's body, Wholly iasplanted means that th ©«f re of he device is positioned within the subject's body,

need herein, "charge-balanced" in relation to a DC current is taken to that hs positive o negative: charge int oduced into any system ie.g, a nerve⁾ as a result of a DC current being applied is balanced by the introduction o rise opposite charge in order to chieve overall {net) neutrality,

The carotid bodies i B } are peripheral chemorecsptors that classicall respond to hypoxia by increasing chemosensory activity in the carotid sinus narve ( Sii) _» causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a metabolic sensor i^mplicate in the control of energy homeostasis. Recen ly, the inventors have described that the carotid bodies Stay also be involved in the etiology oi insulin resistance, core raetabolic and hasaodynaiiiic disturbances of highly prevalent diseases like prediabetes, type 2 diabetes, and obstructive sleep apnoea { beiro et al,, 2 13_s which is incorporated herein by reference). In this study, CSN resection, in healthy ra s prevented the development of insulin resistance and hypertensio induced, by subsequent hyperealoric diets. CSS resection prior to hypercaloric diet also reduced weight g in and avoided visceral fat deposition in this viodei > Herein it is demonstrated that CB overact vat ion and increased CS« ■signalling is associated with the pathogenesis of roeuscolic and hemodynamic disturbances , As demonstrated in. the present application, carotid sinus nerve iCSK) activity is increased in anitnal models of issalin resistance: -iaguro χι) < Therefore isodnla ion of the neural activity in the CSS will restit in treat!tSK oi conditions associated with such an i■^••p ired glucose control in a: subject. Further, aboiishxsent of CB activity by hyperopia art lioratas glucose toleranc in type 2 diabetes patients ί era- Cbuz, Guerreiro, ftifoeiro, Guarino: and Conde [in print] , Advances in ox eri!!!sntai Medicine and Biology: Arterial Chemoreeeptors i Physiology and Pathophysiology; Hyperbaric oxygen therapy improves glucose homeostasis in type 2 diabetes subjects: likely invoivetaent ot the carotid bodies, incorporated herein by referenced .,

Therefore, rn accordance with a first aspect of the inven io there is provided an device for inhibiting the neural activity of a carotid sinus nerve iCSb'} of a. subject, the device comp ising! one or more transducers configured to apply a signal to the CSii or associated carotid body of the sub ect, optionally at least two such transducers; and a controller coupled to the transducer or transducers, the controller controlling the signal to be applied* by the one or acre transducers,_: such that the sign l isoduiates the neural activity or the CSfi to produce a physiological rasponss n the subject, whereirs the physiological res ons produced in t e subject is one or more of the g oup consisting, of; eduction in sympathetic tone, increase in insulin sensitivity, decrease in insulin resistance, increase in glucose tolerance, a d cti n in visceral fat mass, a reduction in subcutaneous 5 fat t»®ss, reduction in plasma catecholamines, reduction in tissue catecholamines, reduction in urinary matanephrines, a reduction in glycated haemoglobin iHhATc ) or ¾ reduction in eiroulaciog triglycerides. Preferably the physiological response is one or more of, sore preferably ell of, increase in insulin sensitivity, decrease in ins-ilixi resistance, and increase in gluc se tolerance..

Ϊ0 In certain embed. imsiiss, the signal applied by the one or mere transducers is a nondestruc ive signal .

in. certain such embodiments, the signal applied by the One or m re transducers is an electrical signal, an electromagnetic signal, an optical signal, an ultrasonic signal, or a thermal signal. In those emixidiments in which the device bass at leasS 15 t.vo transducers, the signal which each of the transducers is configured to apply is independently selected from an. electrical s gnal, an optical signal, n ultrasonic sign l, and a thermal signal. That is, each transducer may be configured to apply a different signal. Alternatively, in certain emhodifaents each transducer is c figured to apply the same signal .

20 In certain embodiments, each of: the one or move transducers »ay be comprised of cue or more ei&ccrodes, one o more photon sources; one or ac ultrasound transducers, one -ss re sources o heat, or one or more other types of transducer arranged to put th signal into effect.

In certain embodiments, he signal applied by the one or wo e transducers is an 25 electrical signal, for exam le a voltage or current. In certain such embodimen s the signal applied comprises a direct current Cj , such as a charge balanced direct current, or an alternating: current {AC} waveform, or both a D and an AC ¾aveforax,

in certain ewbodimen s the electrical signal applied fey the one or more transducers 30 has a frequency of 0.5 to i km_f optionally 1 to 50 Wis, optionally 5 to SO KHa_:, In ceroain embodiments the signal has a frequency of 2% to S&kH^'a, optionally 30- ¾SkKa, In certain embodiments, the signal has frequency of ll-ln S¾i«, Is certain eebodiments, the eiec riesX signal has a frequency of greater than ikKa. It is sftowft herein that electrical signals having a frequency of more than 20kB« are 35 particularly effective at inhibiting (in particular, blocking! neural activity of one CSX, Therefore, in certain preferred embodiiaer.fcs. the electrical signal has a frequency greater than 20kHz,. optionally at least 2$ kKs, optionally at le st; aiikHi. in certain embodiments the signal has. a frequency of .lOkHs, 40kHr or S3¾H¾. in ceroain embodiments, an onset response as a result of the signal being applied 40 can be avoided if the signal does not have a frequenc of 20fci¾ or lower, for example .t- 20k&s, or ;· XO .Ho.

In certain eol;odiments the DC waveform or AC waveform may be a square, sinusoidal , triangular or com lex waveform. The DC waveform nsay alternatively be a constant amplitude waveform, in certain embodiments the electrical signal is an AC 4S Sinusoidal waveform.

It will be appreciated by the skilled person that the current amplitude of an applied electrical signal necessary to achieve the intended neuro»odula ion will depend upon the positioning of the electrode and the associated electrophysiological characteristics <e.g. impedance) , it is within the ability of 50 the skilled person to determine the appropriate current amplitude for achieving the intended neurcexxsuia ion in a given subject. For example, one skilled person is aware of methods suitable to monitor fc.ha. neural activity profile induc d by nauromodulacion .

I certain embodiments, the electrical s 6sX has a ur ent, of 0_:.S-5nA, optionally .δ..5«ί¾«2«ί¾, .o ionally i S~l.SmA, optionally 1mA or ¾sA.

S Sr. certain em odiments, the signal is an electrical signal corsprisiog an A:: sinusoidal w veform having a frequency of greater than 2SkHs , optionall 3c-50kKs. Id certain such embodiments, the signal is a electrical s gnal comprising ar; AC si.ti.ujSMda1 waveform, having a frequency of greater than 2¾kKx, optionally lO-Sobhs having a c.uv .··<··;·:". of injA .or 2m&,_:

0 in those embodiments in which the signal applied by the ne o more transducer is an electrica signal, at least one of the one or tacxna- transducers is. an electrode configured to. apply the electrical sig al, in certain such erieoditsents , all the transducers are electrodes configured to apply an electrical signal, optional iy the same electrical, signal■

S In those embodiments where n the signal is as electrical signal and each transducer configured to apply the signal is an electrode, the electrode may fee a bipolar electrode, or a tripoiar electrode. The electrode taay be a cuff electrode or a wire electrode.

In certain embodiments wherein the signal applied by the one or more transducers is0 a thermal signal, the signal reduces the t m erature of the nerve {i.e. cools the nerve; - in certain sxsc embo iments the nerve is cooled to 14*0 or lowe to partially inhibit neural activity, or to 5 ¾ or l ver, f r example 2 °c, to folly inhibit neural activity. In. such mbodim n s, it is preferably not to cause dam g to the nerve,. In. certain alternative embodimen s, the signal increases · the5 temperature of the nerve ii.e, heats the nerve} . In certain emfcodimeats, neural activity is inhibited, by increasing the nerve by at least S *C, for example by ¾ ^''C, St, 5¾, 8 ¾. In certain embodiments, the signal both heats and cools the nerve, sissultaneoasly at different locations o tise nerve, or sequentially at the same ct different location on the nerve.

0 In those e-;-boaiments in which the signal applied by the oije or snore transducers is a thermal signal, at least one of the one or more transducers is a transducer configured to apply a thermal signal, in certain such embodiments, all the transducers are configured to: apply a thermal signal, optionally the same thermal signal .

5 In certain embodimen s, esse o snore of the one or more transducers comprise a Peltier element conf igured to apply a thermal signal, optionally all. of the one Or more transducers comprise a Peltier element. In certain esribo iFftenta, one Or more ot the one or wore transducers comprise a laser diode configured to apply a thermal signal, optionally all of the one or more transducers comprise a laser diodeD configured to apply a thermal signal. In certain embodiments, one cur wore of the one or more transducers comprise a electrically resistive element configured co apply a thermal signal , optionally all Of the one or more transducers comprise a electrically resistive element ccniigured EO apply a thereal signal:,

in eec-.aiu embodiments the signal applied foy - he one or more transducers is a5 mechanrcai signal . In certain embodiments, the mechanical signal is a pressure signal. In certain such embodiments, the transducer causes a pressure Ot at least 250iftmhg to foa applied to the nerve, thereby inhibiting neural activity. In certain alternative embodiments, the signal is an ultrasonic signal. In certain gueh embodiments, the ultrasonic signal has a f equency of 0. S- 3. OKHs , optionall 0.S-0 l,¾MHs optionally l.liiiz. In certain embodiments, the ultrasonic signal has a density ot 10--IOO ¾?/c«a^s _< for exampl 13,6 H/o;«^s οτθ.¾ Vt/cm^. In certain, embodiments the signal applied by the one or more transducers is an electromagnetic signal, optionally an optical signal. Irs certain such embodiments, the or-e or taore transducers comprise a laser and/or a light eiftitting diode configured to apply the optical signal. In certain such embodiments, one optical signal {for example the laser signal) has an energy density from SOQ Si/cac t 9QQ In certain alternative embodiments, the signal is a magnetic signal. In. certain such embodiments, the magnetic signal is a biphasic signs! w th a frequency of δ-ΰΰΚχ, optionally 10H.K. In certain such eafcadiaiSTi s, the signal has a pulse duration of i-iOOihiS:, for example SOOjiS- In certain, embodiments , the physiological response may he temporary, that ia, upon cessation of c e signal, the measured, physiological parameter i:rs which an improvement «s induced by the signal returns substan ially towards baseline neural activity within I-an seconds, or within i-60 minutes, or within 1-24 hoars, optionally 1-12 hoars, optionally Ι-δ hoars, optionally i-4 hours, optionally 1.-2 hoars, or wit in 1~? days, optionally 1-3 days, optionall 1-2 days, . Xn som instances, the physiological parame er retu ns substantiall foll to baseline neural activity. Tha is, the value of the physiologioal parar&etar following cessation of the signal is substantially tha same as the value for the physiological parameter prior to the signal being applied ·· i.e. prio to Ksodula ocv,

in certain embodiments, the physiological es onse ttiay be persistent. That is, upon cessation of the signal, the value of the msasareable physiological parameter remains substantially the same as when the: signal was bein applied - i,¾. the value for the physiological parameter during and following modulation is substantially the same

In certain embodiments , the physiological response may he corrective. That is, upon cessation of the signal, th value of the m.easureable physiological parameter mora closely esembles the value for that parameter observed in a heal thy subject than prior to modulation, preferably substantially fully resembles the value for that paranseoer observed in a healthy subject.

in. certain einbodiments , the device further comprises means to detect, one or more physiological parameters in the subjec . Such me ns ma be one or more detectors configured to detect the one or more physiological parameters. That is, in such embodiments each detector may detect more than one physiological pa ame e , for example all the detected physiological parameters . Alternativel , in such embodiments eac detector is configured to detect a separate parameter of t&a one or more physiological parameters detected.

la such certain embodiments, the controller is coupled to the iaeans. to detect one or more physiological parameters, and causes the transducer o transducers to apply tiis signal when the physiological parameter is detected to be meeting or exceedin a predefined threshold -value .

in certain embodiments, the one or more detected physiological parameters comprise one or more of the group consisting of; sympa hetic tone, plasma insulin concentra ion, plasma glucose concentra ion, plasma catecholamine concentration ii.s^, one or more of epinephrine., norepinephr ne, matanephrine , normetanephrine and dopamine; coneant tion, tissue catecholamine concentration, plasma Khccic conce ration or plasma triglyceride concentration.

In certain embodiments, the one or more detected physiological parameters comprise an action potential or pa tern of action potentials in a ner e of. the subject, wherein the action potential or pattern: of action, potentials is associated with the condition associated with an impaired response to glucose that is to be treated. In certain snob embodiments, the nerve is a sympathetic: nerve, m certain such emhodi enus, tna nerve ie a splanchnic sympathetic nerve. In certain embodiments. the :v:-;.ve is the e oneal nerve, the sciatic nerve lor one or w e i:ussch¾o; thereof;, or muscle sympathetic nerve terminals, in certain alternative _:suoh embod ment's , the ner e is an afferent; nerve involved in metabolic regulation, for example <^■■::■;^■>:-,:·:. nerves from: the liver or from the ill tract, In one desirable eniodimeac, the ne ve is the CSK. In this amfoo i eurc , the detected pattern of actios potentials may b« associated with impaired response to glucose or insulin.

It will he app eci t d that any two or more of the indicated, physiological a am te s assy be detected in parallel or consecutively. For x mple, in certain e bodime ts, the controller is coupled to a detector or detectors configure to detent the pattern of action potentials in the CSX at the. same time as glucose tolerance iix the subject.

The modulation in neural activity as a result of applying the Signal is inhibition of neural activity in the CSfi . That is, in such embodiments , application of the signal res-alts in the neural activity in at least part o£ the CSN being reduced comp red to the baseline neural activity in that part of the nerve. Such a reduction in activity could equally be across the whole nerve, in whic case neural activity would be reduced across ths whole nerve. herefore, in cer ain s c embodiments, a result of applying the signal is at least partial inhibition of neural activity in the CSh, In certain suc embodiments a result of applying the signal is at least partial inhibition «f neural activity in the ebemoreceptor branch of the CSN, In certain such ersbodiraents , a result of applying the signal is full inhibition of neural activity in the ehemorecepfor branch of the CSK. In certain embodiments , a result of applying the signal is full inhibition of neural activity in the CSM.

ϊη certain embodiments, the modulation in neural activity as a resul of applying the signal is a block on neural activity in the CSK^'. That is, in such erobodirae.nts , the application of the signal blocks action potentials f om travelling beyond rise point of the hiooh i at least a part of the CSM. In certain such embodi ents, the modulation is a partial block. In certain alternative embodime t , the modulation is; a full block. In a preferred embodiment, the modulation is a partial or full hlooii. of neural activity in the CSS.

In certain embodiments, the modulation in neural activity as a result of applying the signal is as alteration to the pattern of action potentials i the C8N. in certain such embodiments, the neural activity is modulated such that the resul ant pattern of action potentials in the CSK resembles the pattern of action potentials in the CSiS observed in a health subject,

modulation of neural activity may comprise altering the neural activity in various other ways, for example increasing or inhibiting a particular part of the activity and s imula ing new elements of activity, for example in particular intervals of time, in particular frequency bands, according to particular patterns and so forth , Such altering of neural activity may for example represent befcn increase and/o eatresses wi h respect to the baseline activity.

In certain embodiments of: the method, the signal is applied intermitten ly. In certain such embodiments, the signal is applied continuously for at least S days, optionally at least 7 days, before ceasing . That is, for such intermittent applisat on of the Signal _< the signal is applied continuously for si: least S days (optionally 7 days), then application ceases for a period se.g, 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month; before the signal is again applied continuously for at least S days (optionally 7 days) .

In certain such embodiments wherein the signal is applied intermittentl , the sugnsl is applied for first time period, then stopped tor a second ti«a period, men reapplied for a third time period, then stopped for a fourth time period. In such an embodiment,, the first, second, third and fourth periods run sequentially a d consecutively. The series of firs , second, third sad fourth, periods amauxsts ta one application cycle. In er ain so-eh: embodiments, multiple application cycles c rs run consecutively such chat he signal is applied in phases, between which phases so signal is applied.

la such embodiments, the duration of the first, seeosd, third aisd fourttt time pexiodg is nde endently selected. That is, the duration of each time period may he tne same or different to any of the other ti» periods. Is certain such ecRGodiraent a , tte duration of each o.E t e f rst:, second, third and fourth t me periods may foe any time fro .1 second is? to 10 days (d) , 2s to ?d, is to 4d, 5s to 2.S h urs i24^'h) , .30s to 12 h, .1 tain to 13 h, S min to 8 h, ¾ min to 0 h, 10 tain t 6 ■n, it) in to ^'4 h, 30 mln to 4 h, 1 h to 4 h. In certain embodiments, the ^'duration of each of the first, second, third and fourth time periods is 5s, 10s, 3OS, 60s, 2 min, S tais, 10 rain, 20 min, 30 min, 40 ra n, SO min, 60 min, 90 sssin, 2 h, 1 , 4 h, >V h, e h, 7 h, 3 h, $ _t. 10 h, 11 h, 12 h, 13 h, i¾ h, IS fe, 16 b, 1? h, 18 h, IS !:·. 20 n,_: 21 h, 22 h, 25 h, 24 h, 2d, li. <3d, Kd, ed , 7d.

In certain embodime ts wherein the controller causes the signal t be applied incert-ittently, the signal is applied fo a specific amount of time per day. lis certain such aiabodime«ts, the signal is applied for 10 HII S, 20 min, 30 min, 40 min, 50 rain, C min, 90 n n. 2 h, 1 b, 4 h. 5 h, S b. 7 h, S h, 9 h, 10 h, 11 h, 12 . a , 14 h, IS h, is h, 17 h, 18 b, 13 h, 20 h, S h, 22 h, 23 ¾ per day. \ certain such eaxbod.iments, the sig al is applied con inuously for the specified amount of time. In certain alternative such embodiments, the signal may be applied discontiouoasly across the day, provided the total time of application amounts to th {specified time,

In certain a&i odi.ments wherein the controller causes, the sigttal to be applied intermitten ly, the signal is applied only when the subject is in a specific state. In certain such embodiments, the controller causes the signal to be applied only when, the subject is awake. In certain alternative embodiments, the controller causes: the signal to be applied only whan the subject is asleep. In. certain embodiments, the controller causes the signal to he applied prior to and/or after the ingestion of food. I certain mbodim n s , the controller causes the signal to be applied prior to and/or after the subject, undertakes exercise.

in certain such embodiments, the device further comprises an inpu rseans. In such embodiments, the status of: the subject (i.e. whether the subject is awake, asleep, pre- or post-eating, o pre- or post-taking exercise) can be input into the device by the subject or by a physician. n alternative embodiments, the device further comprises a detector configured to detect th status Of the subject, w e ei the signal is applied only when the detector detects Chat the subject is in th spec fic state,

In certain alternative embodime s,, the controller causes the signal to be continuously applied to the CSN and/or carotid body. It will be appreciated that in esdtodicaents wherein the signal is a series of pulses, gaps between pulses do not mean the signal is no continuously applied. Such continuous application may continue indef initeiy e.g. permanently. Alternatively, the continuous application may he for a minimum period, for example the signal may be continuously applied for at least S days, or at leas ? days.

In certain embodiments of the device, the inhibition in neural activity caused by the application of the signal J whether that is an inhibition, block or other modulation of neural activity} is. temporary/ reversible . That is, upon cessation, of the signal, neural activity in the narve returns substantially towards baseline neural activity wsthin l-SO seconds, o within, i-%0 minutes, or within 1-24 hours, optionally 1-12 hours, optionally l-S hours, optionally 1-4 hours, optionally 1-2 hours, or within 1-7 days, optionally 1-4 days, optionally 1.-2 days,. In certain such embodiments, the neural activity returns substantially fully to baseline neorai activity. Tha is, the neural activity following- cessation of the .signal is su stantially the same as the ne r l activity ' rior to the signal being applied ~ i.e. prior to wodulation.

IK arta n- alternative embodiments, the inhibition in neural activity caused by the application, of. the signal is substanti lly persistent. That is, u on cessation of the signal, neural activity in the nerve re^gains substantially the same as whsn the signal was e ag applied - i.e. the neural activity during and following modulation ia substantially the same .

In certain embodiments, the inhibition in neural activity caused by the application of the s gnal is partially corrective, referably substantially corrective. Tha is, upon cessat on of the signal, beurai activity is. the nerve more clossely resembles the pattern of action potentials in the CS observed in a healthy subject than prior to modulation, preferably substantially uily resembles the pattern of action potentials in the CS^ observed in a healthy subject. In such ejab &bsen s, th modulation caused by the signal can be any aoduiation as defined herein. For example, application of the signal cay result in a block on neural activity, and pon cessation of the signal , the pattern of action potentials in the nerve resembles the pattern of action potentials observed in a healthy subject. By wa of further eaareple, application- of the signal may result modulation such that the neural activity resembles the pattern of action potentials observed in a healthy subject:, and upon cessation of the signal, the pattern of action potentials in the nerve resembles the pattern of: actio potentials observed in a healthy subject. It is hypothesised that such a corrective effect is the result of a positive feedback loop - that is, the underlying disease state is treated as result of the claimed methods, and therefore- the ehemosensory signals along the CSS are not abnormal, and therefore the disease state is not perpetuated by one abnorsial CSN neural activity.

In certain embo iments, the device is suitable for at least partial implantation xnto the subject such that at least a portion of the device sits within the body, prefer-ably in pros siity to the C8JS or carotid body t which the s gnal is to be applied. In such em odime ts, parts of the device, for ex m le the transducer and the controller, ma be suitable to be wholly implanted in the subject such that the signal can be applied to the CSH or carotid body, and other parts of the device ma be external to the body, for exam le an input element or remote charging element. In certain mbo iments, the device is suitable to be wholly implanted in the subject.

in certain embodiments , the device further comprises one o more of a power supply el!-:·--::.·-.:.- . tor example a battery., and/or one or mare commu ication elements.

In a further aspect, the invention provides a tiochod for treating a conditio associated whth impaired glucose control in a subject, the method, comprising implanting a device according to the first aspec , positioning at least one transducer of the dev ce in signalling contact with a CSli and/or carotid body of the subject, and activating the device.

The invention also provides a me hod of inhibi ing neural signalling in the CSN at a subject comprising implanting in the subject a device according to the first aspect, positioning at least one transducer of the apparatus in signalling contact with a CSt^; or carotid body of the subject and activating the apparatus. In certain e:r:-ol.;;ua u of this method, the inhibition of neural signalling in the CSS improves glucose control rtt the subject,

to such e-sbodisaents, the transducer is in signalling contact with the CSli or carotid bod when it is positioned such that the signal cap be affec ively appl ed to the CSJJ o carotid body. The device is activated when the device is in an operating state such that the signal will be applied as determined b the cOfsh.roller . X» certain embo ime ts of these me ods, the method is applied bilaterally, T ar is, iii such siabodimen , a first transducer is positioned in signalling^' contac with the left carotid sinus nerve (CS») and/or 1©ί?Κ carotid body of said -sub ec to ∞odi*2a e the neu al activit of the left CSH in. the subject, and a second transducer is positioned, in signalling contact w the right carotid sinus nerve rC ii; aud/or right carotid body of said subjec to modulate the neural activity f the right CSS .^■ r, the subject. X» certain such embodiments, the firs a d second transducers are part of one device according to the third aspect, in alternative such emtbodiments, the first and seeotid tratssdude^'rs are part of separate devices according to the third aspect.

Implementa ion of all aspects of the invention (as discussed both above and faelcv?) will be further appreciated by reference to Figures XA-iC.

Figures lA-XC show bow the im-ention way be put into ©fleet using one or more nearoiuodalatio!j devices which are: ifssplanted in, located on_< or otherwise disposed wire respect to a subject 200 in order to carry out any ot th various methods described herein. In this way, one or more neuromoduia ion devices can be used^' to x¾af a condition associated with impaired glucose control in a subject, by odulate fj¾ carotid sinus nerv® afferent neural activity.

Xn each of the Figures lA-XC a separate neuroKsed lation device ISO", χ_:;0θ^{, !} is provided in respect of each Of the lef and right carotid .sinus nerves, although as discussed above a device could be provided o used; i respec of onl one o£ the left and right nerves. ^'Each such nenromodulatioTi. devi.ee may be fully or partially implanted in the subject,, or otherwise located, so as to provide neuromoduia ion of the respective carotid sinus nerve., carotid sinus body,, or both. Figure 1A also shows schema ically cowpenents of one of the neuromoduia ion devices 100, in which the device comprises Several el«Eaents, cocRponants or functions grouped together in a single unit and implanted in the subjec 280, A. first such eiew nt is a transducer l«¾ which is shown in p oximity o a carotid sinus nerve 90 f the subject. The transducer a.02· may be operated by a eontroiler element X04, The device say comprise one or atore further .elevents such as a communication elem nt ass ,, a^' detector element i18, a power supply elem nt 110 and so f:orth. Each of the left and right neuromcdula ion devices 100', 100' ' may operate independently or may operate in communica ion with each other, for example, using respective communication elements 10$.

Each neuromodulation device ISO', X00^{, !} may carry ut the required neuromoduia ion independent iy, or in response to one or wore control signals. Such a control signal i!iay be provided by the controller 104 accordin to an algori hm, in response to output of one or more detector elements 108, and/or in response to communications f om one or mo e external, sources received using the communications element, ¾s discussed herein., the detector element i s} could be responsive to a variety of different physiological parameters.

Figure 18 illustrates some ways in which the device E Figure .la m y be differently distributed. For example, in Figure IB the neuromoduia ion devices 100' , X00'' cotiprise transducers 107. implanted proximal iy to the carotid sinus n r es 90 or bodies. Out other elements such as a controller 104, a ccmmuni cation element l&S and a power supply i.XO are implemented in a separate control unit. 30 which fra also be implanted in, or carried by the subject. The control unit 130 h n: controls the oransdaeers in both of the neuro oduiation devices via connections 132 which ma lor e¾aiiipie comprise eiectr.i.oa.1 wires and/or optical fibres for delivering signals and/or power to tee transducers .

Xn the arrangement of Figure 18 one or more detectors 108 are located separately from the control unit, although one or more such detectors could also Or instead foe located within the control unit 1 0 and/or in one or both of the neuromodal nion devices las ' , 10Q^{: >}, The detectors may be used to detect one or more physiological arameters of the subject, awd the controller eieme.nc or control v*nit ea ca ses the transducers t apply the signal, in es onse to the detected parameter ί s 5 , for example only wheo a detected physiological a am t r meets or exceeds a predefined threshold value. Phy sioiogicai parameteris which could, be detected for such purposes; i.:v ·«:.!<: sympathetic one , plasma insulin concern rati n, insulin sensitivity, plasma glucose eonr-ehtratidn, gluc se ole ance, plasma catechoistiine concentration, tissue catechola ine concentration, plasms BfoAl ;.· concentration and lasm triglyceride concentration- Similarly, a detected physiological parameter coyld be an action, o ential or pattern of action potentials in a nerve: of: the s bj ct .. for esample ars efferent o m re particularly a sympathetic nerve, wherein the action potential or pattern of ac ion potentials is associated with the condition to be treated. It is cie-nocstratod herein that neural activity irs the Sfi is increased its animals in a prediafoetic state _> and thus, in one ©tsbodimetst , the Or each, detector icm way he located on or proximal to the CSK, such as to detest the action potential or pattern of actios potentials irs the CStS, as indicative of a disease state. In one emfoodrmeiit, d tector 108: ^»¾* · he imptartceid unilaterally an or proaimai to one ;i,e. lef or right} of the CBN (or, analogously, the CK, or the branch of the glossopharyngeal nerve to the CSK/C8, or the ehemosensory branch of :·>·.;· H : , and the or each transducer 102 fs foe irnparited o or proaimall to the other of the SM (or analogous nerves; ,

a variety of other ways; in which the various functional elements coul be located and g ou ed into the oe«romodalat on devices, a control unit 130 nd elsewhere are ^•of. course possible . For example , one or w e sensors of Fi ure IB could be need in the arrangement of F g res 1A or 1£ or ctifoer arrangements.

Figure 1C illustrates some ways in which some functional icy of: the device of Figure lA or IS is provided not implanted in the subject. For e¾a« e_> irs Figure .tc an external power supply 140 is provided which can provide power to implanted eleoents of the device in ways fasiiiar to the skilled pers n, and an external controller 15ft provides part or ail of the functionalit Of the cOotroller 104, sod/or provides other aspects of control of the device, arid/o provides data readout from the device, and/o provides a data input facility 1S2. The data inpat facility could be used by a subject or other operator in variou ways, for exam le to input data relating to the subject's current or espected activities such as sleep, eating, or physical exertion.

Kaon i!euromodpla iqn device itay foe adapted to carry out the neuroftsoduXat ion required using one or wore physical tisodes of Operation which typically involve applying a signal t a carotid bod or sinus nerve, such a signal typically involving a transfer of energy to Cor from), the body or nerve. As. already discussed, saeh modes >»ay comprise ^■••odulating the carotid sinus ne ve o body using an electrical signal, an Optical signal, an ultrasound or other mechanical signal, a thermal signal, a magnetic or electromagnetic signal, or soste other use of energy to carr out the required modulation. Such signals ^'may he non- destruc ive signals. Such modulation ma comprise increasing, inhibiting, or otherwise changing the pattern of neural activity in the nerve or body. To this end, th transducer 90 illustrated, in Figure IA could foe comprised of one or more electrodes, one or mors photon sources, one or more ultrasound transducers, one more sources of heat, or one or more other types of transducer arranged to put the required neuromoduiation into effect,

The neural modulation device's? Or apparatus may be arranged to inhibit :oeural activity of a carotid sinus nerve or carotid food by using the transducer is- to apply an electrical signal, for example a voltage or current, for example a direct current i.DC} such as a charge balanced direc current, or a AC waveform, or both. In such embodiments, the transducers configured to apply the electrical signal are elec rodes . In cer a n embodiments, the electrical^' signal applied .by the one o:r more transducers as &_: frequency ,o£^" e,S » iO kV.z, optionally 1 to S kHs, optionall^y S to so KH3. in certain eifi oaimeii e the signal has a frequency of 25 to: SSklis, optionally 30-SS:ki¾, In. certain embodimen s, the signal has a fr q ency of δ-10 kBa. I certain embodiments, the electrical signal has a frequency of greater than leu ia, optionally at least 25 ki¾, optionally at least IQkHa. n .certain eitbodiraen S: fc¾a signal has a frequency of IGkHa, 40¾H3 or S kH^y .

In pertain erasediisents, an onset response as a result of the signal being applied can toe avoided if the signal does not have a frequency of 20kH;z or lower , for exaivcfia l-23kHa, or l-lQkRa.

la certain erabodi.ttents the DC waveform or AC waveform may be a square, sinusoidal , rrianasilar complex wav€-f.oir > The DC waveform «iay alternatively be a constant .smp itxxie- waveform.. In certain e:nbo i"¾;u.s the electrical signal is an AC sinaaoida1 yeforre ,

It will ha appireoi.ated fay the skilled person tbat the current aitpiitude of an applied electrical signal necessary to achieve t: e intended neuromoduiatioa viili depend upon the positioning of t e electrode and: the associated electrophysiological characteristics '{·«,ø.. i¾¾sab!aaeei . It i within th« ability of the skilled person to deterstine the appropriate current m litude for ac ieving the intended neuromodulat ieu in a g ver, subject. For exam l , the skilled parson s aware of methods suitable to monitor the neural activity profile induced by necrofssodua iop_*

In. certain etsboa is-seacs . the electrical signal has a current of ϋ,1-1δί¾ optionally D,5-SEii«., optionally lf«A--3mA, optionally ImA or 2st&.

la certain ewtbodiiftents, tbe signal ia art electrical signal comprising an AC sinasoldal waveiorss having a equ nc of greater than 2¾kBt , optionally SO-SOkHa,

In those embodiments wherei one or ¾ore transducers are electrodes, the electrode stay be a bipolar electrod j or a tripolar electrode, late^' electrode may be a ·..-:; ·^'. ί electrode o a wire electrode,

Thermal methods of neuyomodulation typically manipulate th temperature of a serve to inhabit signal propagation. Fo example, Patberg et ml. {Blocking of impulse conduction in. psrrpberal ne ves b local cooling as a routine in aniaal experimentation. Journal of S arosefence Methods 1384 ; 10 : 2S7-7S , which is incorporated herein by reference) discuss how cooling a nerva blocks signal conduc ron without an onset response, the block being both reversible and fast acting, with onsets of «p to tens of seconds. Heating the nerv can also be used to block conduction, and is generally easier to in¾>lew«nt in a small impl ntable ¾r localised transducer or device, for example using infrared radiation from, laser diode or thermal heat source sach as an electrically resistive element, whiob can be used to provide a fast, reversible, and spatially very localised heating effect ^■see for exareple Duke et a! , tf Neural Eta . 2013 Jun ; 9 ( 3 i 0:3«_.0_:δ3 Spatial and temporal variability in response to hybrid electro- optical stimulation., w ich is incorporated herein fay reference) . Either Leaning, or cooling, or both could be provided using a Peltier element,

fe eertaxn embodiments wherein the signal applied by the one or mare transducers ia ¾ thermal signal, the signal reduces the temperature of the nerve ii,e, cools the nerve! ^, in certain such ©ssfo dimencs tfee nerve is cooled to i¾¾ or lower to partially inhibit neural activity, or to 6 "¾ or lower, for example 2 , to fully inhibit neural activity- In such embodiments, it is preferably not to cause damage co the nerve. I certain alternative atioodime ts .. the signal increases the temperature of the nerve U,e. heats the nerve). In certain eitbod ments , neural activity is inhibited by increasing the nerve by at least 5 ¾, for example fay 5 5 ¾, ? *c, .8· "C. In ce tain esibodim a s* the signal -both beats and cools the iiSrw, sitvt itaneoosly at different locations on the nerve, or sequentially at the same or a sferen- location on the nerve.

In those; embodime ts in which, t e signal applied by the one or more transducers is: a thermal signal, at least one of the one or siore transducers is a t ansducer configured to; apply a thermal signal. In certain such embodiments, «11 the transducers a e configured to apply a thermal signal, optionally the saine thenaai signal .

i certai embodiments, one or more o the one or more transducers comprise a Peltier element configured to apply a cherasal signal, optionally ail of the ore or mora transducers comprise a Pel ier element. In certain emfoodlmencs, one or snore of the on® or isore tt-aasducers Comprise a laser diode conf igured to apply ¾ thermal signal, optionally ail of cb:«- one or w re transducers comprise a laser diode config re to apply a thermal signal . I certain eifibodinseats, one or more of the one or »rs transdneers comprise a electrically resistive element configured to apply a. thermal signal, optionally all of the one or wore transducers comprise a electrically resistive element configured to apply a thermal signal.

Optogenetic pharmacology for control f native neuronal signaling proteins.

Kramer KHet ai, which is incorporated herein b reference 5.

In ce t .··. embodiments the signal applied by th one or more transducers is an electromagnetic signal, optionally an optical signal. In certain such embodiments, the one or isota transducers comprise a lager and/or a ligh emitting diode config red to apply the optical signal, la certain such embodiments, the optical signal if or exaxsple the laser signal} has an energy density from SO& vi co* co Soo i/cm^:\ In certain alternative eiKbodiments , the signal is a t«agnetic signal. n certai such embodiments , the mag etic signal is a biphasic signal with & frequency of 5-lSHs, optionally lOKsm in certain such embodiments, the signal has a guise duration of l-iOOOixS, for example SOOjiS.

in certa n embodiments the signal applied by the one or ore transducers is an electromagnetic signal, optionally an optical signal. In certain such embodiments, the one or more transducers comprise a laser and/or a light emitting diode configured to apply the optical signal., in certain such embodiments _f the Optical. signal if.or xam le the laser signal; has an energy density from So0m¾/cm^;: to 50G ii/enC^, In certain alternative embodiments, the signal is a magnetic signal. In certain such embodiments, the magnetic Signal is a foiphasic signal ith a frequency of $-.i5U¾, optionally lO.Hs . I certain such

the signal has a pulse duration of Ι^ΐϋϋ μ^, for ex ple soo.ttS,

Mechanical forma of neoromodulafeico can include the use- of aitrasound which may conveniently fee impieii-ehted using external instead Of implanted ultrasoand transducers. Other forms of mechanical neuro^.odnhat ion include the use of pressure tier example see "The effects of compression upon conduction in myelinated axons of he isolated frog sciatic nerves* by Robert Fern and V, J. Harrison Bt.j. Ansesth. 11973} , 47, 1123, which is ioc rporatedi herein by reference.

Zxi certain:; embod ments the signal applied by the one or vaoxn transducers is a me ani l signal- in certain embodiments, the mee a»i«ai sign l is a pressure s.:.gh3l. in certain such emhodir^mts, the transducer causes a pressiite of at least 2^'.¾-&ta«!H$ to ha applied to the nerve, thereby inhibiting neural activity. In certain alternative embodiments, the signal is an ultrasonic signal,. In certain such embodiments, the ultrasonic signal has a frequency of <K5~2,0MHz, optionall 0.5- l.SMKz, optionally Ί . IKHa . In certain eaa&odicaers s, the nlfcfasonic signal has a density ot 10·· 100

for exemple 1 .» W sa' or S3 »/c« .

Sosse other electrical forms of nearomodulation wa use. direct current it-C⁾ , or alternating current ;AC; waveforms applied to a nerve using one or more electrodes. A OC block ma be accomplished by gradually ranging u the DC waveform amplitude sShadra and Xilgore, 1S8S Transactions on Neural systems and rehabilita ion engineering, 2CS4 .12 (3d 313^» 24}.

¾ s»e other kC echn q es include tiW t or KH?AC ihigh~freqaency or kilcharts frequency] to provide a reversible block {for exa ple see Kilgore an Badra, 2004, Hedicai and Biological Engineerin and Computing, m i4Zm ί·334··40$. Kesve conduction block utilising high-- requency alternating current,

Kilgore XL, Bhadra In the work of Kilgore and Bbadra, a proposed waveform was sinusoidal or rectangular at 3-5 kHz, an typical signal amplitudes that produced; biock ware 3 - S Volts or 0.3 to 2.0 arilli Amperes peak to peak.

H AC may ::y ;...:ai i.y be applied at a frequency' of between 1 and 50 κΚ« at « duty cycle of: 180% (Bbadra, ίΐ,. et ai . , ournal of Computational Kearoscieoce , 2007, 22(3) , pp :>';.>· s2»: . Methods for selectively blocking activity o a: nerve by application of a wav fo m having a frequency of S - IS kHz arc described ia US ?, 3_:e.S,14$ . Similarly, US S , ?3i,S7S describes a rcschod of ameliorating sensory nerve pain by applying a S-SD fcJ¾ frequency wav fo m to a herye .

'80m commercially available nerve blocking -systems include the Maestro (STH^:i system available frot: Bnteromedic® Inc. of Minnesota, USA . Similar nearomoduiatiou devices are more generally discussed in US2014/2:1.4129 and elsewhere.

In a further aspect, the invention provides a method of creating a condition associated wit¾ impaired glucose control in. a subjec , the method comprising applying a signal to a carotid sinus hervs (CSS} and/or a carotid bod of said subject to nsod&iate the neural activity of a CSK in the subject, in certain embodiments, this can be accomplished by the signal being, applied by a reuromoduiatio device comprising one or rapre transducers tor applyin the signal. n certain preferred embodiments the neuromodula icn device is at least partiall implanted in the subject. In cer ain preferred embodiments, the neuromodulation device :; wholly implanted in the subject ,

As is known by the skilled person, each individual mammalian subject has a left and a right carotid body, each carotid body having an associated CSS. The CS>; carri.es afferent nerve signals tram the carotid body to the brain. Therefore, in methods according to the invention, the signal can be applied directly to a part of or ail of one or both SS to modulate the neural activity in that or those CShs. Alternatively, the signal can be applied to a part of or all of one or both carotid bodies associated with the CSMs in order to modulate the afferent nerv signals carried f om: the carotid body or bodies to the glossopharyngeal nerve and. the brain stem. Alternatively, the signal can be applied to a part or ail of both the carotid body and the associated CSS, unilaterally or bilaterally.

In certain embodiments of the method_., the condition associated with impaired glucose control is a condition associated wi h insulin resistance, Ex mples of. co a ci nsr associated with impaired gluc se control include metabolic syndrome, type diabetes, o esi y, hyperte sion, d siipidaemia , sleep apnoea syndrome aid other metab li disorders. In certain embo iments, the condition treated by the ss& hois is at le st one of the -group consisting of. metabolic syndrome, type 2 S diabetes, obesity, and dyslipidasmia, Ths skilled pars n will apprecia es h&t any one subject:, can ex bit one or more conditions associated with impaired glucose ont ol and that the metho can be used t treat on or more or all of those con itions.

Is certain efnbod me ts «f the met od, treatment of the condition is indicated fcy a0 improvement in a measurable physiological .parameter, for example, redaction in s mpathetic tone, increase in insulin sensitivity, increase in glucose tolerance, a ed cti in total tat mass, a redaction in. visceral fat mass., a reduction in subcu aneous fat ssass, reduction in plasma c techol mines , reduction in. tissue catecholamines, reduction in. urinary mstahephrines , a reduction in. glycatedS haemoglobin. {.HbAl.d ) or a redact ion in circulating triglyceride concentration. Is certain such embodiments, the measurable physiological paramete,r^' ia at least one or the ^'gr up. consisting of; sympathetic tone, insulin sens tivity, glucose sensitivity, total fat mass, visceral fat mass,, subcutaneous fat mass plasma cat echo! aminos concent;, tissue catecholamines cent -.use urinary metanephri aa0: content, and levels Of. glycated haemoglobin (HfeAXCi - In such embodiments, sympathe ic tone is understood to be the neural activity in sympathetic nerves arid or associated sympathetic neurotransmitter measured in systemic or local tissue compartments in the sympathetic nervous system,

Suitable methods for determining the v&lua for any given -parameter would be5 appreciated by the skilled person. By way of example, an increase in heart rate and/or blood pressure for a period a least 24hts is typically indicative of an increased sympathetic tone, as is aberrant heart rate variabl ili , cardiac or renal norepineph ine spillover, skin or muscle micronedrography and plasma/urine norepinephrine By way of further example,, insulin sensitivity csn be measured by0 the HCeiA ixidsx or by a hyparinsalinemic clamp, Sy way of further example, total tat ass may be determined by bioimpe ene . Sy wa of further example, visceral fat can foe indirectly determined by measuring abdominal perimeter. Further suitable methods for determining the value lor airy given parameter would be appreciated by the s-tilled person.

5- In certain embodiments of the method, treatment of the condition is indicated by an improvement in the profile of neural activity in the CSN. That is, treatment of the condition is indicated by the neural activity in tbe C.SSJ approaching the neural activity in healthy indi idual.

In cettaxn embodiments, the physiolog cal response may be temporary, that is, upon0 cessation of the signal, the measured physiological parameter in which an improvement was induced by the signal retains substantiall towards baseline neural activity within I-S0 seconds, or within 5.-60 minutes, or within 1-2-4 hoars, optionally i-vs hours, optionally hours, optionally 1-4 hours, optionally i-2 tours, or within i~7 days, optionally 1-4 days, optionall 1-2 days, . In some5 instances, the physiological parameter returns substantially fully to baseline neural activity. That is, the value of the physiological parameter f llowing cessation of the signal is substantially tbe same as the value for the physiolo ical parameter prior to the signal being applied - i.e. prior to modula ion,

0 in certain embodiments, the physiological response may be persistent, Tlsat is, upon cessation of the signal, the value of the measureabie physiological parameter remains substantially the same as when the signal was being applied - i.e. the value for the physiological parameter during and following modulation is substantially the same if: embodiments, the physiological response may fee corrective:. That is, upon cessation of Che signal, he value of trie maasureabl physiological parameter m re closely resembles the value fo that parameter observed in a healthy subject than prior to modulation, preferably substantial iy fully resembles the alue for that paraxteter obser ed in a healthy subject .

In certain ®robodit»ent£5 of the wthod, he saetliod does; not affect th cardiopulmonary regulation func on of the carotid body and CSS. In particular embodiments, he method does not affect one or mo e physiological parameters in toe subject selected frosa the group consisting of ; p02, pCC2 , blood p ess re, oxygen demand and cardio-respiracory responses to exerc se and alt tude.. Suitable mecbod* for^{^} de rmin ng th value for any given parameter vonld be appreciated by the skilled person.

According to the method of the inven ion, applicatio of c.».e signal results in the neural activity in at least part of the CSX being reduced con-pared to the baseline neural, activity in that part of the ner . Such a reduction in activity could equally fas across the whole nerve, in which case neural activity wo ld be ed ced across the whole nerve. Therefore, in certain such embodiments, a result of applying the signal is at lease partial inhibition of neural activity in the C8K . In certain such eaboditsencs a result of applying- the signal is at least partial inhibition of neural activity in the chemoreceptor branch of the CSS. In certain, such embodiments, a result of applying the signal is full inhibition of neural activity- i the chamoreceptor branch of the CSN. In certain efnbe-dirnen s, a result of applying the signal is full inhibition of. neural activity xn the CSS, Analogously, in certain embodimen s the modulation in neural activity as a result of applying the signal is inhibition of neural activity from the carotid sinus/carotid body to the glossopharyngeal nerve and the brain s em,, such that neural activity which is associated with the CSN/CS i.n the CSN_S. the glossopharyngeal ne ve or- the brain stem is reduced compared, to pre-treat ent neural activity associated with: the carotid sinus/caro id body in that part of: the ne ve ,

In certain embodiments of the method, the modulation in neural activity as a result of ap lying the signal is a block on neural activity in the CSX . That is, in such embodimen , the application of the signal blocks action potentials fxous travelling beyond the point of tb block in at least part of the CSS. In certain such embodiments, the modulation is a partial block. In- certain alternative embodim nts,, th modulation is a full block.

Xn certain embodiments of the method, the moctul¾tior» in neural activity as a result of applying the signal is an alteration to the pattern of action potentials in the CSii. In certain such embodiments, the neural, activity is modulated such tha the resultant pattern of action potentials in the QSti resembles the pattern of action potentials in the GSif observed in a healthy sybject.

In certain embodiments of the met od, the signal is applied intermittently. Xn certain such embodiments, the signal is applied continuously for at least S days, optionally at least 7 days, before ceasing. That is, lor such intermittent application of the signal, th signal is applied continuously for at least S days ^{optionally ? days?,, then application ceases for period (e.g. 1 day, 3 days, 3 days, 1 week.. 2 weeks. I month) before the signal is again applied continuously for at least S days (optionally ? days; ,

In certain such embodiments wherein the signal is applied intermittently, the srgoal is applied for a first time period, then stopped for a second t me e iod_; then reapplied tor a third time period, then stopped for a fourth time period. In iShoh an embodime t , toe first, second, third and fourth periods run sequentially and consecutively. The series of first, second, third and fourth periods amounts to one application, cycle^, m certain such embodiments, multiple application cycles can run consecutively such that the signal is appl ed ia hases, between which phases no signa s a pli d.

In such em odiments the dura ion of the first, second^, third snd tourtfc tiiss periods is independently selected. That is, the duration of each time period wa he c^'Sie same or different to any of the other fcltae periods. Is certain such embodiments, the duration of each of the first, second., third and fourth tir&e periods may be any eim« from 1 second is) t 10 days (di , 2s to ?d, 3s to 4a, Ss to 2 hours !2 hi , ; 0:5 t 12 .h, 1 tain to IS h_f 5 tdn to 8 h, 5 min to 5 h,. 3.0 edn to 6 h, 10 min ^■■: 4 h, 30 sain to 4 , .· h to 4 . In certain embodiments, toe duration of each of ^■■::.■: first, second, third and fourth time periods is 5s, 10s, 30s, 60s, 2 ^• _>;vin, 5 «tin, X& min, 20 a rs, JO tain, 40 «vin, SO win, 60 min, 30 min, 2 h, i h, 4 h, $ h, € h, 7 h, 0 h, 9 h, 10 h, IX b, 12 h, 13 h, 14 h, 15 h, l£ h, I? h, 18 h, IS h, 20 , 21 h, 22 fa, 23 h, 24 h, 2d, 3d, 4d, Sd, Sd, 70.

In certain embodiments wh rein the signal is applied intermi an l * ;:be signs! is applied for a specific amoun of time per day, la certain snob embodiments, the signal is -applied for 10 win, 20 rain, 30 win, 40 rain, 50 win, 50 rain, 5 njin, 2 «, 3 h, 4 h, S h, δ h, 7 h, 8 ¾, 3 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 15 h, 10 h, 20 , 21 h, 22 h, 23 h per day. In certain such eehodi&erits, the signal is applied continuously tor the specified aeiovmt of time, lo certain alternative such embodiments, the signal say be applied discon inuousiy across the day, provided the totei time of a plicatioh amounts to the .specified time.

In certain embodiments wherein the signal is applied intermittently, the signal is applied only whe the subject is in a specific state. In certain such embodiments, the signal is applied only when the subject is awake . In certain alternative embodiments, the signal is applied only when the subject is asleep. In certain embodiments, the signal is applied prior to and/or after the ingestion of food. In certain embodiments, the signal is applied prior to and/or after the snhjeot undertaxes. exercise. In such embodiments, the status of the subject (i.e. whether the subject is a«ake_; asleep, pre- or pos -eating, or pre- Or po t -taking exercise; can be indicated by the subject. In alternative such embodiments, the status of t e subject can be detected independently oK any in ut from the subject. In certain embodiments; in which the signal is applied by a neurotnodaia ion device, the device further comprises a detector configured to detect the status of the subject, wherein the signal is applied only when the detector detects that the subject is in the specific state.

In certain alternative embodiments , the controller causes the signal to be continuously applied to the CSti and/or carotid body. It will be appreciated that in embodimen^ts wherein the signal is a eerres of pulses, gaps between pulses do hot mean the signal is. not continuously applied. Such continuous application may continue indefinitely, e.g. permanently . Alternatively, the continuous application may be tor a minimum period, for example the signal may be continuously applied for at least 5 days, o at least 7 days.

In certain embodiments of the method, the modulation in neural activity caused by the applica ion of the signal {whether that is an inhibition, block or other iKoduiation of neural activity} is temporary/ eversible . That is, upon cessation of the signal, neural activity in the nerve returns substantially towards baseline nearai activit wichin 1--60. seconds, or within · 50 minutes, or wi hin 1-7 days, optionally 1-4 days, optionally 1-2 days, o within 1-24 hours, optionally 1-12 hours, optionally 1-5 hours, optionally i-¾ hours, optio ally 1-2 hours. In certain such embodiments, the neural activity returns substantially fully to baseline neural activity. That is, the neural activity following cessation of the signal is substantially tne same as the rseoral activity prior to the signal being applied - i. e, prior, to modulation. In certain alternative embodiments of Che method, the modulation in aassrai activity caused by the application of the signal is siibstan.tr ially persistent. Sat is, upon cessation of the signal, neural activity in the nerve remain substantially the «am.e «¾ when the signal was being applied - i.e. the neural activity during and following modal at i n is substantially the Basse.

i certain embodiments of the machod. the ttodulation in neural activity caused by the application of the signal is partially corrective, preferably substantially corrective That is, upon cessation of the signal, neu al activity in the nerve more closely resembles the pattern o£ action potentials: in the CSii observed in a healthy subject than prior to modulation, preferably substantiall fully resembles the pattern of action potentials i the CSS observed in a healthy subject. In such embodiments, the modulation: caused fey the signal can be any modulatio as defined herein. For exam le, application of the signal ma result in a block on neural activity, and upon cessa ion of the signal, the pattern of action .poten ials^' in. the nerve esembles; the pattern of action potentials observed in a healthy subject. By way of further example, application of the signal may result ioadnlafion such that the neural activity resembles the pattern of action potentials observed in a healthy subject, and upon, cessation of the signal, the patter of action potentials in the nerve reseenlea the pattern of action potentials observed rn healthy subject. It is hypothesised that such a corrective effect is the result of a positive feedback, loop - that is, the underlying disease state is treated as re ul of the clas.med methods., and. therefore the chetaose.osot-y signals along the CSH. are not abnormal , and therefore the disease state is not perpetuated by the abnormal CSS neural activity,

In certain embodim t of method according to the invention, the method further com rises the step Of detecting one or were physiological .parameters- of the subject, wherein the signal is applied only when the detected physiological parameter meets or exceeds a predefined threshold value, in su h- embodiments wherein more than one physiological paramete is detected,: th signal way be applied when any one ot the detected parariteters meets or exceeds its threshold value, alternatively only when ail of the detected parameters iaeet or exceed their threshold values. In certain, embodiments wherein the signal is applied by a neuromodula icn device, the device further comp ises at least one detector c tfigured to detect the one or »f>r« physiological paramete s.

in certain embodiments of Che rec.hod, the one or more detected physiological parameters are one of more of the group consisting of; sympathetic tens, plasma insulin concentration, insuli sensitivity, plasma glucose concentration, glucose: tolerance, total fat mass,, visceral fat mass, plasma catecholamines {i.e. one or more of epinephrine, norepinephrine, i^'se ariep ine , normetaoophrine and dopamine) content, issue catecholamines content urinary me anephrine content, plasma Hhftlc content and a reduction in Circulating triglyceride concentration.

K way of example, a typical KfoAlc content in a healthy human subject would be between .20-42 mmo /mol (4-8% of total Hbl . An HbAlc content exceeding 42«8aoI/mol may be indicative of a diabetic state..

Is-^, cer i embodiments, the one or more detected physiological parameters are one or more of the group consisting of: sympathetic tone, plasma: insulin concentration, plasm glucose concentration. plasma catecholamines (i.e. one or more of ep- nephrite, norepinephrine, metanephrine, normetahephriue) concentration, tissue catecholamines, and plasma lihalc cox;taut .

In certain embodiments, the detected physiological parameter is an action potential or pattern of action potentials in a nerve of the subject, wherein the action potential or pattern of action potentials is associated with the condition associated with an ittpaired response to glucose that is to fee treated. In certain such embodiments, the nerve is a sympathetic nerve. Is certain such embodiments, the nerva- is an afferent sympathetic nerve, In certain such embodiments, the nerve is he CSS . ¾ this eififeodimenc, the detected pattern of act ::>::■ potentials wa be ssociated with impaired response to glucose. In certain alternative such embodiments,, the nerve is an afferent ne ve invclved in xsetahclio regulation, for example afferent nerves fro® t e livisr or from the 01 t act.

I& certain l ernati e such em odiments, the nerve is an efferent sympathetic nerve, optionally the peroneal nerve, the sciatic nerve {or oxie or snore branches thereof;, or muscle sympathe ic nerve r cmiRals . In certain such exabodir«ents, the nerve is the sciatic nerve. In certain such etaboditaests, the nerv is the renal nerve .

It will be appreciated that any two or more of the indicated physiological a me ers may e detected in parallel or consecutively. For example, in certain embodiments, the pattern of action potentials in the CSS can toe detected at the s ws time as glucose tolerance.

la certain such embodiments, once first applied, the signal may be applied in ertntcentl or permanently, as described in. the embodiments above.

as demonstrated herein, stopping or inhibiting neural signalling in one CSfi {i.e. unilateral soduiation) is sufficient to a least partiall restore insulin sensitivity ί Figure 10} , although this effect may foe transient. Therefore in certain smcodimeSt^'s , a signal is applied to a carotid sinus nerve {CSS5 and/or a carotid body of said subject to modulate the neural activity of a CSN in the suteiect. That is, the signal is applied at least unilaterally to achieve at least unilateral {i.e. right or left side* modulation of neural activity in the respective CS . In Figure 9, it is clear that stopping neural signallin in both C;ldS (i.e. bilateral modulation; produces a greater effect that is longer-lasting. Similarly, ¾··.. a res 2s and 21 show that bilateral block of CSK xieural activit using: an electrical signal is effective at restoring glucose tolerance and insuli sensitivity. A greater improvemen is observed the longer the block is applied iPiware 20} .

Therefore, in certain preferred embo imen s of the method, the neural activity in both CSfs is modulated {i.e. the modulation is bilateral) . That is, in certain preferred embodiments, signal is applied t the lef carotid sinus nerve (CSttj and/or left carotid body Of the subject and a signal is applied to the right carotid sin s nerve i S i and/or right carotid body of the subje t to modulate th neural activity of the left CSN and right CSK of th subject, la such embodiments , the signal applied to each GS¾f and/dr carotid body, and therefore the type and eatent of modulation, is independently selected fro!i! that applied to the opposite: CS13 and/or carotid body. In certain embodiments the signal applied to the right CSM and/or carotid body is the same as the signal applied to the left CSii and/or carotid body. In certain alternative embodiments the signal applied to the right CSN and/or carotid body is different to the signal applied to the left CSJJ and/or carotid, body.

In certain such embodiments of: the method, a first signal is applied to the left carotid sinus ne ve (CSET) and/or left carotid body of the subject to modulate the neural activity of: the left CS13 in the subject b a neuromoduia ion device comprising one or more transducers for applying the signal, and a second signal is applied to the right carotid sinus nerve iCSli; and/or righ carotid body of s¾id subject to modulate the neural activity of the right CS in the subject by a ne romodula on device c mp ising one or mote transducers for applying the signal. in certain such embodime ts, ths first signal and the second signal, are applied by the same neuromodulation device, tha device have at least two transducers, one to appl the first signal and one to apply the second signal. In certain alternative such mbodiments! , the first and ssseond signals are applied by separate nen ojsodu1at:t.on d vice:; . It should be noted that the temporary oatare of c«e therapeutic effect w en CS activity is sho ped unilaterally ί figure ifi! ssay be date to the total and on^going block of n CS ii.e. by resection) being: compensated for by the remaining CSM. It way be that; intermittent or temporary Unila e al modulation would not exhibit the 5 reduced effect, as che remaining CSN would not be caused to cOKpenBate.

la certain embodiments of the method, the signal applied is a non-destructive srgnal.

in certa n embodiments of the metho according to the -n e:; · on . the sign l applied is an electrical signal, ah electromagnetic sig al i optionally an optical signal),0 a mechanical (optionally ultrasonic} signal, a thermal signal, a magnetic signal or any other type of signal . In certain such eaibodimenta in which mo e than one signal ;say be applied, for exam l one to each CSS and/or carotid body, each signal may be independen ly selected from an electrical signal, an optical signal., an ultrasonic signal, and a thermal signal _< In those such embodiments in which two signals are5 applied by one modulation device, the rwo signals may foe the same type of signal or tsay be different types of signal independently selected from an electrical signal, an optical signal, an ultrasonic signal, and a thermal signal. In those embodiment :in which two signals are applied, each by a separate peurpmodnlation device, the t¾o signals may foe th same type of signal or may be different types of signal0 independently selected from an electrical signal , an optical signal, an ultrasonic signal, and a thermal signal.

in certain embodiments of the method the signal is an electrical signal, for example a voltage or a current , and comprises one or wore AC or DC waveforms. In certain embodiments, the electrical signal i an AC wavefbrra. having a frequency of0 0,S to 18.0 kHz, optionally 1 to SO kHz, optionally 5 to 50 KHx. in certain embodiments the signal has a frequency of 25 to 55 kite, optionally ,30-SS kHz. In certai embodiments, the signal has a frequency of 5 -IS KH^'r.. In certain embodimen s, the electrical signal aas a £rega«ncy o£ greater than ikHss.

It la sh w herein that electrical signals having a frequency of more than SOkKxt> ar_:s: particularly effective at inhibiting (in particular, blocking) n&orai activit of the CSH, Therefore, in certain preferred embodiments of the method the electrical signal has f equency greater than 20kH¾, optionally at leas 3.5 kHa, optionall at least .30fcH¾, Xn certai eoood^ n the signal has frequenc of 3.sxKs, QkHa o SOkHa.

0 In certain embodiments., an onset response as a result of the. signal being applied can be avoided if the signal doss not have a frequency of: ^:zokifz or lower, for exarvple l-SOkHs, or i-10K55z.

in certain embodiments the DC waveform or a waveform may be a square, sinusoidal, triangular or complex Waveform. The DC waveform may alternatively be a c nstant5 amplitude ¾av«forrn. In certain embodiments the electrical Signal is an AC sinusoidal wa efo m:.

it: will be appreciated by the skilled person that the current amplitude of an applied electrical signal necessary to achieve the intended neuromoduiation will depend upon the positioning of the electrode and the associated0 electrophysiological characteristics /e.g. impedance? . It is within the ability of the skilled person to determine the appropriate current arRplitade for' achieving the intended nearomodnlation in a given subject. For example, the skilled person is aware of methods suitable oo monit r the neural activity profile induced by neuroKodulatioa - la cer ain ars dims s , the electrical sianal has a current of 0.5--¾mA, optionall δ.¾«Α-Ώ«Α, optionally ,S-1.5m¾, optionally lm¾ or 2mh.

In certain i iOdimenrs_s the signal is an electrical signal eomprisisg an ac sinusoidal waveforti having a frequency of greater fc.ha_:n. SSkHs, optionally - SSKKK . In certain suc embodiments_., the signal is an electrical signal comprising an AC sinusoidal w ve o m having a frequency of g eater than 2SkHsi, optionall

having a correne of 1mA or 2mA.

Sa those embedments in Which the electrical signal; is applied by a neoromodul ion device comp ising one or more electrodes _f eac transducer configured to apply the signal is an electrode confi red to appl the electrical signal. In cer ir, such embodiments, all transducers are electrodes ooufigarap to apply an eXacfrical signal, optionally t e: same elect s\io«i aignai.ln certain such embodiments, the: electrode may b a bipolar electrode, or a tripolar eXecfcrqde, The electrode may foe a caff electrode or a wi e electrode.

!!■ certain ambpdimexits wherein the sigxsal applied by tha ope oo: more transcpK:«rs is thermal signal, the signal educes the temperature of the nerve (i.e. cools the nerve)„ In certain such embodiments the nerve is coaled to 14¾ or lower to partially i hibit neural activity, or to € ¾ or lower, fo example a ^';C_; to fully inhibit nearal .activity. In such .embodimen s, it ia preferably not ;o ..cause damage to the nerve. In certain alterna ive embodiments, the signal increases the tempe ture of the nerve ii._:e. heats the narre . Irs certain embodiments , neural activity is inhibited by increasing the nerve foy at least 5 ^SG, for exa ple by 5_.¾, s: ¾ ? ¾, 8 ^s€. in certain embodiments, the signal both heats and. cools the nerve.,_: aimultaneoaal at differen locations on the nerve,, o sequentially at the same or oiffareiat location on the nerve,

in those embodiments in wiiich tha signal .applied by tha one or more transducers is a thermal s gnal , at least one o the one or more transducer is s transducer: configured to apply a thermal signal. In certain such embodiments:, all: the transducers are configured to appl y a. thermal signal, optionally the same rnerriisl signal .

So certain embodimen s, one or mor of the one or More transducers comprise a ¾eltier element conf igured to apply a therm l signal, optionall all of the one or ec ;··=· transducers comprise a Peltier elsment. In certain ecibodiitents , one or more of the one or mora, transducers ooisprise laser diode: configured to apply a thermal signal, optionally all of the one or more transducers comprise a laser diode configured to apply a thermal signal , la certain embodiments, one or ore of the one or mo e t ansducers comprise a electrically resistive element configured to apply a t ermal signal, optionally ail of the one or more: transducers comprise a electrically resistive element configured to apply a thermal signal .

la certain ©mbodinssn s the signal applied by the one or more transducers is a mechanical signal. In. certain embodiments, the mechanical signal is a pressure signal. In certain such embodimexitjs, the transducer causes pressure of at leas iiSO mKg ·. c be applied to the nerve, chereby inhibiting neural, activity. In certain al ernative embodiments, the signal is an ultrasonic signal. In ce taiis such, embodiments, the ultrasonic signal has a frequency of 0 , S-2 , ΟΚΗκ, optionally 0.5- 1.5MHz, optionally I.IMH*. In certain esKbo3iments_f the ultrasonic signal has a density of ϊθ-ΐθθ^' W/cm^s, for example 13,6 W/c«r orSS W/eftf.

in certain embodiments the signal applied by the one or more transducers is an electromagnetic signal, optionally an opi:icai signal. In certain such embodimen s, the one or taore transducers comp ise a laser and/or a light emitting diode - 2$ - cc-nt inured to apply t e optical signal. In certain such e bodimexsts , the optical s;i:¾n.ai ifox exam le the laser signal) has an energy density fros? seOsaK/csr^' t© ¾S0 S ffi*. la certain alternative emfoodiffients, the signal is a magnetic signal. ¾ cer ain such embodiments, the._: fita¾necic signal is a iphasic signal with a irecmeney of -lbAz. optionally Ι.Ο_.Ηκ, I ertai such_: emhod xKests, the Signal has a phise duration Of X-1.00Q;J.S, or ex m le SOOaS.

¾s a l rche aspect, the inden ion provides a neuromodulatory electrical ¾¾veior¾ .for se treating insul n resistance in -a subject, e ei the waveform is a k loHertH alternat ng current {AC} w veform: havixig a frequency i 1 to SO KHss, optionally IX-SikH;; . e ch that, whan applied, to a carotid sinus: nerve cSSM) i the subject, the waveform inhibits neural signalling in the CKK. la certain e:!i cidi;;;¾hts, the waveform, when applied, to tha_. CSSf* imp ov s the auDlec 's: response o na l in .

la a further aspect, the invention provides use of nenrosnodulatioa device tor creating a condition associated with impaired glucose control in a subject such as insulin resistance, by modalating .afferent neural activity in a carotid sinus nerv« ot the subject.

Based on the observations presente herein, in particular the observation cha C¾-; dene v tions results in lowering of the circulating plastssa t iglyceride concentration, it will be appreciated that in a still further aspect, the invention provides a i:;echod of treating obesity in a subj c , the taethod cossprisiog applying a signal to a carotid sinus n rve (CSS; and/or a carotid body of said subject CO modulate the neural activity of a CSS in the subject. Further scill, in ancthst aspect, the invention, provides a method of treating obesity, the method cossprisixjg applying a tiana to a carotin sinus nerve iCSSTi and/or a carotid body- of said Subject to modulate the neural activity of a CS¾ in the s.tfb¾«ct_< wherein the signal is applied by a ne ro odulatiqn device comprising one or more transducera for applying the signal . The ernhodi enfeis presented above with respect to the third and fourth aspects of the invention will be applicable, mutatis jsaKawSi-s, to these aspects of the invention.

In a preferred .embodiment of .all aspects of the invention, the subject or patient is a m m al , more preferabl a hurrsan, In certain erabodiffients, the subject or patient is suffering from a disease or disorder associated with impaired glucose control .

The loregoing detailed description has been provided by way of explanation: and illustration, and is not intended to 1 ;.···.: r. the scope of the appended elaiii;e. Many variations in the presently preferred embodiments illtiStrated herein will be apparent to one of ordinary skill i the art, and regai withix; the scope of the appended claims and their equivalents.

Sxawpxa Ί-

&ni¾i .ls ¾rt exporlisenfc&l p oce ures

Srpe i^pBents we e performed in male Wista rats 1200- 80g)„ aged 3-9 weeks, .obtained front the animal house of the ϊίσ?¾ Medical School, NOVA University Of hi soon. The animals were k pt under tessparature and humidit control SihiiS* humidityS with a h iight~l2h dark cycle. On the day before the ex eri ent l procedures, r-ats were fasted overnight and allowed free access to water, ¾_ree different groups of aniitais were use throughout the experiments; a control group, a prediabetes group and a type 2 diabetes group. The control group was fed a sham diet i?.4 fat plus; ?S% carbohydrate 1 % sugari plus 17% protein; SDS diets mi; Probiologica, bxsbon, Portugal). The prediabetes group fed a 00% lipid rich diet during at leas 3 week-? (.60* fac plus 17% carbohydrate pl s 2 % protein; ucedola, M^'ilari., Italy! ~ & high fat: {HF> diet:. This prediabetes model resembles prediabetes ra humans ass it is chaPactariped fo byperln UX.in:emia_f insuiiri resistance, and nor ogiycesisia (Figure 4) . Tne type diabetes rsspdel was fed with a &0% lipid rich diet («P% fat pins 17% carbohydrate plus ,23* protein; ucedolap ilan, rtsly) plus_. 35% of sucrose: in lx.u;k;ug ¾ i>;: at least 1 weeks ~ a high fat and. high sugar {HF-r-Hsui diet, this model resestsfoies an initial phase of type £ diabetes in humans add it is characterised foy combined, hyperglycemia,, insulin resistance, glucose intolerance sad hypsrinsulinemia iia Fleu^'r et 2011; i?iqvx .2, 5 and 6) .

wistar raps were subt-itted to HP diet lor at least 3 weeks to induce prediabetes slid to HF--:Ksu diets for at least 14 weeks in order t induce type diabetes and ·„·.··:;··· than submitted to foi lateral carot d sinus ne ve resection under ketamine t3¾-ag/k ) /p.ylaaln:e ;4sg/kg> aneathesis nd forypenorphina (To^g/kg; analgesia as described in Ribeiro at «1-, 201.3,. which is incorporated herein by reference. The cont ol groups were submit,ted to a sham procedure. Food _:a¾d liquid intake were monitored during the treatments i all .groups of aniaiais,

A cer the surgical procedure- t¾e anitaals were kept nder the respective diets to maintain, an increased caloric ingestion during the recovery perxod and the remaining experimental period (3 weeks for the prediabetes ra del and II weeks; for the type 2 diabetes model) . Fasting glucose (Figures 8_. and s for type 2 diabetic rats, igxtce 4 for prediabetic rats), glucose tolerance ( igure 10 for type 2 diabetic rats) and insulin sensitivit (Figures 2 and 3 for type 2 diabe ic rats and Figure 4 for diabetic rats) were evaluated before and attar the carotid inus nerve denervation. CSN resection was confirmed through the absence of ischemic h oxia - induced hyperventilation assessed as occl sion of common caxOtid artary (Kxfoeiro et ¾!., 20135- Principles of laboratory care were followed in accordance with the European Union Directive tor Protection of Vertebrates Used for Experimental and Other Scientific Ends (201G/S3/£Ui . Experimental protocols were approved, by the ethics committse of the NOVA Medical School, iSOVA Unive sit of L s on.

i4«as« s»i¾n of i»auli» saxssitivity

Insulin aansitivity was de ermined by the insulin tolerance test (ITT . The ITT provides an estimate of overall insulin, sensitivity, correlating well with the 'gold, standard' hyperinsulinemic-eugiycemic clamp (Honssillo ax-d H.amd 0u3, which is incorporated herein by reference). t involves the administration of an intravenous insulin bolus of ii.lu/kg body weight in the tail vain, after an verni ht fast, followed by the measurement of the decline in l sma glucose concentratio Over 15 minutes. e constant rate for glucose disappearance (K_;— > was: calculated using the formula 0.693 ¾■■„, iMensilid ax;d Hamdy 2003; qaarino et ai . C < ; Sibeiro at al., 2C1 ¾ , ail Of which; are incorporated herein by reference; . Slucose half-time (¾₂ί was calculated from the slope, of th least sguare analysis of pl ma glucose concentra ions during the linear decay phase. Flood samples were collected by bail tipping and glucose levels were measured with a gXecometer yihrecision .Xr.ra Meter, Abbott Oiabatee Care, Portugal) and test strips ΐAbbott Diabetes Care, Portugal S <

igure S shows the effect of the HF+Hau diet on insulin sensitivity. Type 2 dj.ahaoiP: rats exposed to the HF+Hsu diet exhibit a significantly diminished rate for the clearance of glucose comp red to control rats fed a normal diet,: thereby indicatin a reduction in sensitivity to insulin ;i,e, insulin resistance or tolerances as a result of the SPtHsu diet:, similarly, Figure ¾ shows that prediabetic mice exposed to the H diet also exhibit a red ction in sensitivity to insulin, The ability of CSS resection to restore sensitivity to insulin in both type 2 diabetic and prediabetic models is shown in Figure .¾ and Figure 4, respectively, where insulin resistant rats from both models that have undergone bilateral CSN resection exhibit insulin sensitivity comparable to control rats fed a nortaal die ,

Figure 12 shows the effect of bilateral {A) and unilateral {&) CSS denervat on on insulin sensitivit in predigbetic rats, f gure 12 shows that insulin sensitivity is restored one week after unilateral denervation (i.e. only one CSN is resected). This effect is lost by 2 weeks post-denervation, likely due to compensa ion via iccreased activity in the other CSN. However, it is expected that a partial or tempo ar unilateral odulation of CSN neural activity (i.e. of only one CS i would not result in such compensation. Figure I2 shows that bilateral denervation effectively restores insulin sensitivity. This effect is siaiutaxneb until at least 3 weeks post -denerva ion,

eas reweiifc of fastiag glucose a»<t glucose tolerance

Qiueose tolerance was evaluated toy Shte oral glucose tolerance test iOSTfS . A glucose solution C2g/kg ody weight} w s a ministere intrsgastrically by oral gavags after an overnight fast (Car.taseosa efc. al , , 2001), Blood samples were collected by tail tipping and glucose levels were measured with a glucome er (Precision xtra Hater, Abbot Diabetes Care, Portugal) and test strips {Abbott Diabetes Care, Portugal} at 0 {before the glucose load), 15, 30, 60, 120 and ISO !;isi after glucose administration. The evaluation o£ the giycaemia response is performed by calculating the total area under the ae-rut- glucose cur e using the roiniwuro aqnares nsschod or the trapezoids! mat.hod (M tthews et al . , 19 D^:; ., ¾t the end of the QS!T blood was collected by e tail vein to: eppendorfs, Serum samples were oentrifuged in a mierofuge Eppendorf, Madrid, Spain} at X2,000«g for lO siln.

Figures S and ·$ clearly show that a K +Hs diet greatly increases fasting, glucose glycaemia in type 2 diabeti rats, both after 14 weeks and 25 weeks of the diet {Figure- 8}, but that this hyperglycaeffiia is reduced when CSfJ neural activity is pre ented (Figure 5>> . Figure 4 shows that a KF diet does not affect glyeaewig in prediabetic racs, in accordance with the mode! of prediabetes.

Overall tolerance of glucose is also impaired in type 2 diabetic rata fed a MF+Hsu diet< Figure 10.& shows that the total area under the glucose response curve for these type 2 diabetic, rats is much higher than for controls, both at 14 and 25 weeks, indicating an- impaired response to glucose. In Figure 1GB it is shown that for rats which have undergone -CSM denervation after i¾ weeks of a HFVBs diet, the area under the response curve is stftaller. This demonstrates that it is possible to issprove the glucose response by preventing CSS neural activity in type 2 diabetics. e minal Experiment

At the end of the experiments , arterial pressure was monitored in the femoral artery iCoade et al . , 2012 ;: Ouarino et al . , 2013, which are incorporated herei by reference! , After, the rats were killed by an intracardiac overdose of pautopa bicai , except when heart puncture was performed to collect blood, this terisi si experiment was performed with animals under sodium pentobarbital ξ SO mg/kg i.p.i anesthesia, since pentobarbital was shown sot to alter the nietaboiie parameters tested heroin (constant rate for glucose disappearance j¾_mJ., fasting glycecda, insul ine-i-ra , and free fatty acids) in omparison i th conscious animals iOuariuo et al., 2013! or insulin responses to glucose {Davidson, l¾'M, incorporated herein by reference) ,

Measuresiertt ©£ foody we ght and fat laass

Body weaght of type 2 diabetic rats was assessed twice per weak {Figure 6) . These animals tied a Hvilsu diet? exhibited reduced weight gain following CS¾f denervation compared to those anir&als on a KF-s-Hsu diet without CSS? denervation {Figure 6} , Total , subcutaneous and visceral fat we e collected af tar an. abdominal la arotomy arid weighed {figure ?} . Type 2 diabetic rats { lad a HFeKsu diet fo 23 weeks; exhibited an. increase in. total fat compared to control animals . Type 2 diabetic ra;:s that had sadergons CSS denerva ion at 14 weeks e¾fdfei ed reduced fat gain compared to those that had not undergone deservafciea { igure ?.} , In particular, rats in which -CSJi neural activity was prevente exhibited a significant reduction in the level of subcutaneous fat accumulated {Figure 78} -

.S.S5 s own in. Table 1, prediabetie rats <fed a H? diet for « w«¾k.s.> tha had r;dergoxH¾ CSS^' resection after 3 w eks of H diet sK.hifai.-ed significantly reduced w ight gai , had reduced total fat mass and had educed visceral fat mass compared to prad anetic ardtaals chat had not unde gone CS^" denervation. !Tabi 1) . Denervaced HP -diet rats also baa lower levels of low density lipoprotein, - {VCSUi and rS3iyderid s coa-pared to HP-diet rats which had not been deaervated, as well as highe levels ot high density lipoprotein (H^'SXd - Table 1

Tjreafciaesats Control High- at Oi¾fc

Without With OSSS? Without tech CSiS

CSS resection CSS resection

resection r sec ion

Weig gain 0.-S8+0.2 0.38+6, 2 X .«.l.t0,.3^» 0. !i¾0 . ^*

Total fat 51.7±2. 4 V.4.1-6.3 ^■yQ. ui . i** .3: ig/kg)

Visceral fat S.S+0.4 5-5*9... 13.8».8*** 11.0±« .9*

{g kg>

liDL (sig/dl) 4. $±0.3 S ..5*0. £ 4.2±¾ .5 3^,81 - 8

srou i^g/dl) 28. Oil .2 23,3+1,2 20.3*1.2··** 25, Oil .$*

Triglycerides 31.1*3.5 20.4:12.7 45.4±3.4* liJ<8±S . * ( -g d j

Effect of carotid sinus serve resection on weight, otal fat, visceral fat and lipid profile { total cholesterol, triglycerides, HDL and hDld in control and h igh fat diet rats. Data with and withou carotid sinus rsssec ion are means of S--9 and S-10 val es, respectively. One and Two-Way ASOVA with Dunnett's and Bcnferroni. !!sui icomparison tests, respectively; *p<0. OS and *** p<0.C0i vs control; ϋ ίΙ ρ 0. 1 and «8#p<0.001 comparing values with and wi out C H resection.

This shows hat by preventing CS neural activity, it is possible to reduce the rare of ««i¾ix gain, accumulation of fat mass and also .irsprcve the blood lipid profile in m dels of prediabetes.. SKotafoly, the circula ing triglyc ride: content was reduced i^'a resected rats versus those which had CSK intact in both the control and igh-f t die groups. This suggests that the device and metho s of the invention could be uti ized to reduce circulating triglyceride content. isaasnraiaent of: plasma, insulin, HbAlc, circulating free fatty acids and catecholamines levels,, adrenal atectulla and renal .e*fc«ei-Ola»in« content.

Insulin concentrations are quantified with a ensyma-- linked Immunoso e assay fS&TSAJ kit ' ercodia Ultxase«»ifciv¾ &at Insulin EHSA Kit, Mercodia «B, Uppsala, Sweden?, KhAlc is assessed using a .RA D X kit (R BiOX, Irlando*, P rto, Po ugal} ., ires* fatty acids with a coiorimetric assay (Kenbio, Sorth Carolina, USAi and cortieosterone dete mination erforated with a SetectX corticosterotie Iros-aoriasssay ki (arbor assays, Madrid, Spain).

For catecholamine quantifica ion in plasma, 400 M, plasma samples ars purified and catecholamines extracted and ua t fied as described in Conde et si,, 2012a, which, is incorporated herei by reference. For guaotlf ieation :c£ catechol 3t;in»: content in adrenal medulla, adrenal «;edullai; previously frozen are homogenised in 0,6 K PGA, and their endogenous catecholamine contear w s uantifies* as describe IK Salleg - farci at al,, 20X , which is incorporated herein by .refe ence.

Recordings of carotid stnws nerve activ ty »* vivo

Rats from con rol and prediabetes groups were anaesthetized with . odium erioobatbi a-l isigpa,. Madrid, Spain) i so s¾/kg i-p-i, traeheostosiiaed and the carotid arteries were dissected past the carotid bifurcation. The preparation cs- C'SK was. identified under a dissect ir.g -tieroscope and « block of tissue, including the eap t d bifurcation and she glossopharyngeal nerve:, was removed and; placed in a Lacife ch mbe in ice-cold/X00* Q2- equi l ibrated Tyrode (in m¾.; tJaCl 3.4 ; C^'· S; €a i2 2; i¾oiz H?,?vs 10; glucose ¾.S; pH 7,40} for the farther dissection, Once surgicall cleaned of unwanted surrounding tissue, tbs- preparation CS-CSK was digested during 3-5 mift irs .eollagenasa type 1 ti s¾ ml} solar io so loosen e«« perineurium fConde et al , 2 I2¾>,. incorporate herein by reference > , The ¾B-C.SS^' preparation was maintained in ice-cold 3.80% OS -aqnilifor ted Tyroda until i w s transferred to the recording chawba r . In all instances n mals we e killed by intracardiac: overdoses 0: sodium pentob bital until the baa?, ina OE their hearts ceased.

The GB-CSli preparation was transferred to a_: recording: cham e mounted on a: dissection microscope (itfikor corporation, Tokyo, Japan i and supar used 537*0 with &aca:rbonate/C02 -bat^' fsred saline tin. mKt KaCl 126,· S HCX 2A ; KCl 3; CaCl2 2; ieaCls 1.1; glucose lOr pH 7.40), Recordings of either a single or a few fibers: of CSS were made using a suction electrode. The pipett potential was obtained, with a &K gain, filtered at low frequency ia K¾) and high frequency (¾ kH;si , and recorded at a sample t ecjuenc or 200 .- e. fDigidata IS So , pCiassp; Axon Instruments, Molecular De-vices, >a^;k ^;.agba^;«, IJKS and stored on a computer. Chemoreceptor activity was den ified (as. the sponcaneous generation of action pocentiais at irregular interva sJ and c nfirsssed by its increase in response to hypoxia (normoxia ; 20% 02 + ¾% 02 a 7S% S2; hypoxi.a : ¾% 02 + 5% CC2 balanced S2 or 0% OS *■ S% COS + foalanead HS)- - CSiS unit activity was converted to logic pulses, wh c were s am«3 every second and converted in a voltage proportional to the suts (Figure lid ,

Figure 11 clearly shows that prediab«tic racs (I.e. those that have been fe the HP diet for 1 ^eessi osihihao a different pattern of action potentials in the CSX in response to stimuli. This indicates chat the pathological symp oms of insulin resistaaoe, wetght gain and impaired response to glucose are associated with a. chanase In neural activity in the CSSl Moreover, it is clear from the data described above that preventing this abnormal neural activity iis the CS¾ results in an is!iprovement in. the diabetes-associated symp o s in these rats,. It is therefore possible to treat conditions associated with an irftpaired. response to glucose and with insulin sensitivity (e.g. type £ diabetes) by xaodwlatirra the neural activity in the OsM_< for example .blocking or inhibiting th sign lling, or by altering the_: signalling pa tern -to mora closely resemble that of a healthy subject- Such ffiodiilatipa Can be parforiiiad by a rasurOModuiation device.

Te minal studies of foilateral CSW blocking

Figure 13- shows a flow chart: indicatin the process followed for the expe iments described below.

Sa?:s5 fed a no mal diet ware anaesthetised with arethane Π.Ρ. l.Sg/kg) . £5*3 electrodes were implanted sufocuear.eously across the diaphragm. e CSS «¾s bilaterally exposed and: dissected from underlying tissue. Cor ec caS electrodes ilaxa x Prm-a, bipolar platinum iridium electrodes, AirRay iKieroeoft sling technology; <ss;re implanted bilaterally on each CSli . Tisseei Fibrin glue was used to tooth secure nd insulate the area, his glue prevents excess current spread and. off target :acsoalsr twitches and aw clenching,

io order to eouiiria effective block of CSK neural signalling, hypoxia was used as a sur ogate ;;;odei as detection of hypoxia by the carotid foody leads to neural activity n the CSS , Changes in heart rate and breathing rate were measured as indicative of a response to detected hypoxia. Effective .ock of nearal activity was indicated by a reduction in the relative changes of heart and. breathing rate in response to hypoxia.

A dose response to high frequency alterna ing curren iHFAC} was used to determine the effective parameter of block.- The tested blocking signals were 20 .Hs , aCKHa, 40 H2 and SOKKa, each at Itafc.

Rats were then subjected to 10¾ C_S in t¾ to induce hypoxia and baseline responses to hypoxia were recorded.. Data -os&s recorded toy BMS and ECG f om the surface electrodes and. analysed in KatLab to quantify the heart rate and breathin rate response. Hypoxia led to delayed {fey approximately 30 sscands) increase in respiratory rate and a reduced heart rate (Figure 14 - ho block; . After baseline responses to hypoxia were collected, a dose response to HJFAC was used to determine the effective parameter of block. The blocking signals were 20 Ks, JOKHK, 40KHS, each at wA, and ¾ K¾a at 1 and 2c¾ current, ί Figure 14; >

Whan quantified ! Figure 1SB? , none of the stim lation parameters tested produced 100% inhibition, of the hypoxia res ose, likely due to the compensatory effect of tha central and aortic arch chemoreeaptors . An onset response indicated by an ne ana in breathing rate was observed with a signal of 2 KH« 1-r-A iPignre XSBj , 0.0 or ornimsi onset res onse was observed for the other blocking signals i Figure ISB; . Dating exposure to hypoxia, 30 Kz Xjt>A, -40^'*.¾* IsaA and SSKiic IsrsA and SO KHs 2«ft ail resulted in an effective block of C3N activity, indicate by reduce relative changes in breathing and heart rate in response to hypoxic conditions -Figure l¾Cj .

Reversibility of the block induced by each blocking signal was observed by reassessing responses to hypoxia bmdnute post-block comp red to a sei i::e responses ; Figure l¾.¾p.

f-io effect of H AC between 2O-S0 R¾ was teano en baseline respiratory and cardiac responses ih the aormoKic setting ίFigures 16) .

Surgical m lanta ion and recovery studies

Kats fed a normal diet were anaesthetised with ketswine/medetomidise . Head caps were implanted on the skull, attached to the be;.Tec caff electrodes, and troearred behind the ear and connected bilaterally to th GSNs, and insulated in place by Fi rin glues. Immediately after im lantation n ma s ware s imulated briefl <2 seconds) wi h 30.0-uA at 511?. sp determine correct electrode placement - indisstecS by i c ease i breathing ate {tins was observed in ail animals^} . Anissa^'is- t& allowed to recover for_.10: ays prior co tethered .Mocking.

'··.:· !& days an mals were tethered ^'{and acclimatised for 2 days; and the exposed to a b-iocKi«g signal of SO Ba 3mA sinusoid HFAC continuously fo ? days, >?o behavioural alterations were .siiowa.

llowing cessation of electrical, signal, anit&s3.^:8 mv& exposed to a hy oxi: stimaius and respiratory rate ¾as evaluated wice; at 20 tons post-signal and after on* week. At 20 inutes following, cessation ό£ electrical s gnal, the did o espo d to a hypoxia (10% 02 *90% nitrogen} challenge, demonstra ing that a functional block ¾ss tssaiBtaiaed (Figure 17) . One week af er the electrical, stimulus was stopped, the response to hypoxia had returned to baseline levels {increase in respiratory rate of -20%) ,. indicating the reversibility of t e functional electrical block (Figure 17). The reversibility of the functional block confirms that the functional block produced by electrical signal was not due to damage to the CSK.

Efficacy s udies

^■Ra s unde wen ITT and C- challenges at the baseline, (prior to Hfi-Hsu diet; prior to surgery, pos - urgery, prior to randomisation and after .sha;¾ or active intervention (see Figur 18 for flow series of events} . ¾^■· i »;> i s were anaesthetised with heta iue medetomidine ^'SI. Pi 5 and ead caps were implanted and attached to the COtTec tuft electrodes and trocarred behind the ear and: connected bi laterally o the CSSis, and insulated in place by Fibrin glue. Electrical impedance spec roscopy Was conducted on days 14 and 15 post surgery. ITT was performed between days 1 -is,, and OQTT Petviee days iS-i? post surgery.

he electrical impedance spectroscopy results at 10 days post cuff electrode impl n ation, confirmed that the electrodes were pcs.itioned correctly upon the nerves, and functionin as expected fo their geometry and material composition (average - 0.S h¾s +/ - 1. S ohmsl at lima} (Figure 1(5).

Post-surgical SI T, calculated frc¾i the ITT taken on pose-opera ive days 1 -ig coot irmed that that surgery had minimal impact upon KlTT levels (Figure SO) . &UC of Gl^' pertorifted on days 16- 17 confirmed that glyesemie response to a stim lus was not repscted by surgery.

^■Table 2

&ral glucose challenge test; Area under the C rve (AUC3 of glycaesiiia (mg/dl )

Before 13 weeks of Post sur ery diet diet S re- block}

A e stae intervention group 21437 2 S14 2.¾9fiO

Alio electrical block, acti e il* 2ilii

interven or; ¾ «up tisels were: attached co tethers to allow acclimatisation for 2 days prior to randomisation. Animals were then randomised it?to- two groups: active intervention group ⁽electrical blocking of the CSN using S O HK iSmft)_.; or sham intervention group ^;no electrical block of the CSN 5 , ITT was performed on days s-? and QGTT performed on days 7~^'- . 7-5 daya post r¾ndo«v saoion , T.TT was performed oo all aniia ls frtxa oth g oups aad biTT :¾: :;>uv;! IFigara 205. The K1 T of animals in the s am inter^entxoo aoop xncraaaeo by 18.46% during ch¾ ia aryenoivb jjeriod. This incrftaea was has; oti is;: deal by bignibicant : 0. 43; Th« KXTT of «κίτί;«1ϊ; in the active r:carvar;ti»n group bsscrasaed by 4 ^'?.^'.·¾ % daring the intervimtior; pa^■: : oe.. This booraaae was seat ia'tiealXy sioa Sioaot (p«0 , ibibS ; . Ά trend of incre ing b^'XT with longer dilat n of block was obser ed {Figure 20?

S days; pas?: rssdamiijatioa, OGTT was pari!orfned on aairosla fro;;; the a iv ioteraaption gr . ? days post rarsdoiidsstiott ,- ·:^'.·;^'.¾^".' w s performed on ail animals; £sm bh« aba;;; intervsintion group aaeS Sb« emain ng 3 aeiumls trorn the aaaiba .batoroeo ioa gro p . The ssaaa yc;><r- bo a re:.; under aha carve !AlXTboi. animala in aba;;;. ;;;;yoeoy*;o; ion gro p inexeasied by 1.12% during, the in&aryantion period. This; incre se was; oc btdti sbiaaily significant ip«0. Sid^;-? ; , he Add of. arsi!aais in the sctbaa itrr.erae:ibO:.oh group deareased by^■ . .i d ring rbe ir.r.a;. vsa.r. ; or- roc.od bia deereabe oas ata?: istioal!y significant : p.- 0.3C^:< .^'> ^°

carapid sinus narve, in particular block sta&istieaily ignificant io ro awea s in s;ig oaf Leant ; aprovo-er-ntx i in;;;; in

ioais t ivor .

Tafela 3

Oral giucoas olerance tos-t (OGT i area under t;h® curva i c) for giycaeaia fol owing i:ando»isat or_; ti-i?: .i;i iiX l k g o Ln ^"i?i:v¾ t'.io_*: {^o

Ϊ

Claims

WO 2016/072875 ^• 3? - PCT PT2015/000047

CIAXKS

1. A device ί o in ibi ing the nenrai activity c.i a carotid sinus se i S ) or carotid body of s&bj.eet, the device comprising^;

o © or more transducers configured bo apply a signal to the CSK or associated carotid bod of the sai>3«efc, opti nally a lease Suc transducers; and

a controller couple to the one or more transducers, he controller controlling the signal to he applied by the .©¾£· or m e transd-ueers, such hat the signal inhibits the neural activity o£ t e CSS or carotid body to prbdnce a physiological response ir» ^'the s.ubject,

wherein the physiological respons is one or ore of the group consisting of: an increase in insul n sonsicivity in the sw j&ct, a ;-. ¾s« in glucose tolerance in the subject,, a decrease in fascing} plasma glucose concentration in the subject, a reduction 1» subcutaneous tat content in the subject, and a reduction in obesity in the subject ,.

2, A device according to claim l, wherein the sig-naj is a no dest ct e signal .

j, A device according claim i or claim 2, wherein, the signal is an slectrie&I s gnal, an optical signal, an ai i.-rasonic signal, or a therm l signal.

4. device according to .claim 3, wherein the signal is an electrical signal, and each, transducer configured to apply else signal is an electrode.

5, A device according to claim 4, wherein the ele reds is a bipolar cuff electrode.

e. A device according to claims 4 or 5, wherein the signal comprises; an alternating current (AC) -waveform of greater than kHz frequency.

A device according ¾o claim S, wherein the AC waveform has a frequency ol^: greater than 30kH»>

s. A a :. cc according to claim ?, wherein the AC waveform has a freonency of 30- S.OkHa.

. A :deyice according fco claim S--8, therein the AC waveform is a sinusoidal w eform .

10, A device according to an one of claims 4-o5, wherein the electrical signal has a eurreat of ■"; . ¾ · sS .

11, A device according to any One of claims 1-18 wnerein th signal does not induce .an oisset effec ,

12, & device according to any one of claims i-ij, wherein the apparatus further comprises means to detec on© or mor physiological parameters in the subject .

13, A device according to claim 12, wherein the controller is coupled to said mea s to defec , and causes said transducer or transducers to appl said signal when the physiological parameter is detected to be meeting or ssKceeding a predefined threshold value,

14^, A device according to claim 12 or 13, wherein the one or tnore detected physiological parameters comprise one or mo e of the grou consisting of sympathetic tone, insuli concentration, glucose concentration, lasms catecholamines concentra ion, tissue catecholamine concentration, and plasma HbAlc concentratio . WO 2016/072875 - 3β - PCT/PT2015/000047

15. device according to any one of clairs 12 -14, wherein the on® or more detected, physiological parameters comprise an action potential or pattern of action potentials in a nerve of the subject, wherein, the action potential or pattern of action potentials is associated w the condition associated ith an impaired r sponse to glucose.

16 , A device according to claim I5_f wherein the ne ve is a sympathetic nerve, optionally aa .affe en sym athe ic nerve, optionally a CSS,

11..A device according to any one o claims I -IS , wherein the sigrxsl at least partially inhibits neural activity in the cheRxoreoa tor branch of the CSH., optionally fully inhibits neural activity in the ches ireceptor branch of aha

CSN, optionally fully inhibits neural activity in the CS .

18. A device according to any one of: claims 1-17 wherein the inhibition i neural activity as a result of applying the signal is a partial block or a full block of neu al activity in the CSH .

A device according to an one of claims 1-18, wherein the inhibition in neural activity as a result of applying the signal is substantially persistent .

26- A device according to any one of claims 1-18, wherein the modulation in neural activity is reversible.

21.. A device according to any one of ciaiRiS l-ia, wherei the modulation in neural activity is corrective.

2 . Λ device according to any one of claims 1--21, wherein the apparatus is suitable for at least partial implantarion into the subject, optionally suitable to toe wholly implanted into the subjec .

S3. A Bsethod of treating a condition associated wit iispaired glucos control ia a subject comprising :

i. implantin in the subject a device according to scry one of claims !·■ ix , positioning at least one transducer of the ap ara us in signalling. contact with a SN ox- carotid, foody of the subject;

X i . activating the apparatus.

24, A method f inhibiting neural signalling in the ^'CSif of a subject cosiprising; i. implanting in the snfojact a device according to any one of claims l- 22 ;

i. : . positioning at least one transducer of the apparatus is signalling contact with a CSN or carotid body of the subject;

iii. activating the apparatus.

25, A sca hed according to claim 24 , wherein the inhibition of ueural signalling in. the CSti impr-wes- glucose control in the subject,

M.A method according to claim 23-25, wherein a first transducer is positioned in iaxgnallxng contact with the left carotid siaus nerve {C§Ni and/or left carotid body of said subject to modulate the neural activity of the left c in the subject, and a second transducer i positioned in signalling contact with the righ carotid sinus nerve iCSSi and/or right carotid body of: said subjec to mod late the neural activity of the right CSff in the subject .

27^, A iiiS hod OX treating a condition: associated with impaired glucose control in a subject, the Method comprising applying signal to a part or all of a carotid sinus harve ;θ~Ν; and/o a carotid body of said subject to inhibit the neural activi y of a CSN in h¾ subject.

28. A method according o; clattv 27, wherein the signal is applied by a nauromodaiation device comprising ones or nxsra transducers for applying- the s gnal .

29. A method according t claim 2? or claim 2 , wherein the condition associated sii im aired glucose control is a condition associated with insulin resistance .

jij.A met od according to claim 21-29, wherein the condition is at least one of the g ou consisting of matabolic syndrome, type 3 diabetes, obesity, and dysi ipidaemi .

31, ¾ method according to any one of claims 27-30, wherein treatment of the corsdicion is indicated foy as im rovement irs a measurable physiologies! parameter, wherein said measur ble phy iological parameter is at least one of the group consisting of sympa ise ic ton®,- insulin sensitivity, glucos sensitivity, ί fasting) glucose concent a ion, total fat ¾sss visceral fas sass, subcutaneous fat mass, plasma catecholamines., urinary metahephrluea, and glycated haemoglobin iSb&le) ,

3 , ,¾ method according to any o e of; claims 27-3-1, wherein the method does not affect one or wo e physiological pa amete s selected ·£¾ø» the group consisting of; p0₂, pCO_s, blood pressure, oxygen demand and cardie- respiratory responses to exercise and altitude.

35. A me hod according to any one of claims 27-32, wherein the inhibition Of neural activity as a resul of applying the signal is at least partial inhibition of neural activity in. the CSS , optionally at least partial inhibition of neural activity in the ehemorecepto branch of the CSM, optionally full inhibition pt neural activity in the chempreeeptor branc of: the CSS, optionally full inhibition of. neural activity in the CSK.

34. A method according to any one of eiainss 27-33, wherein he inhibition in neural activity §s» s result of applying the signal is a partial bloeJt or a full block o£ neural activity in the CSi*...

:iS, ssechod. according to any one of Claims 27-3<s, wherein, the signal is continuously applied for at least S days, optionally at least 7 days.

3u , A method according to any one of claims 27-3S, wherein: the inhibition in neural activity is substantially persistent.

37. a method according to any one of claims 27-35, wherein the inhibition in neural activity is reversible.

38. fi. me hod according- to any one of ciai¾s 27-35, wherein the inhibition in nearai activity is corrective.

3$. A method according to any one of claims 27-38, wherein the signal applied is a no -destructive signal.

48, A method according to any one oE claims 27-39, wherein the signal does not induce an onset effect

< 1..¾ ^«;«cbod according to any one of claims 27-40, wherein the signal applied is «« electrical signal, an optical signal, an ultrasonic signal, or a tner::..ii Signal .

*·' ··· · .·^'-. method according to claim 41, wherein the signal is an electrical current and, when the signal is applied; b a neu omodu.lation device, each transducer configured to ap ly the signal i an electrode, optionally a bipolar cuff electrode..

43. A Rsehhod according to claim 42, wherein the signal comprises an alternating currant <AC> waveform of greater than 15p¾x frequency,

44. Λ m hod according to claim 43, wherein the AC waveform has a frequency of greater than 20kH .

¾ . A !isa hoci according to claim 4.4, wherein the AC waveform has a frequency of

.

46., & method according to elaiws 43 4S, the ei the AC wav fo m is a sihpsoidsl waveform .

4". A method according to any oris of cla ms 42-46_» whereih the electrical signal has a current Of Q.S-BBSA.

45. A -method acco d ng to any om.- of claims 37- 7 further comprising the ste o£ detectin ne or more physiological parameters of the subject, whe ein he signal is applied Only: wh n the detected physiological parameter meats or exceeds a predefined threshold value,

4¾. A method, according to claim 48 when dependent on ela ns 28, wherein the nearomoduia ion device fu ther comprises one or more detectors configured to detect the one or roor physiological parameters,

¾Q.A method accord i eg to cl i 48.-4S, wherein the one or more detected physiological parameters comprise at least one of the group consisting of: sympathetic tone, insulin concentration, lucose concentration, plasm Ca echolamines?- concentration, tissue catecholamines c ncencrdt ioh, urinary metanephrrnes concentration, and plasms Hb&Ic concentrat on.

51 » A Method according to ci¾is» 48 -SO, therein, the one or more detected physiological parameters com ise an action potential or pattern of action potentials in a nerve of the subject, wherein the action potential pr pattern of action potentials is associated with the condition fc be treated.

S2. k method according to claim S.I, wherein the nerve is a sympathetic nerve, optionally an afferent sympathetic nerve, optionally a CSS,

¾^'l, A method according to any one of d -its 27-Sl, wherein a_: signal is. applied to a part or ail of the lef carotid sinus nerve iCSK) aad/or left carotid body of said subject and a signal is applied to a part or all oi^" the right carotid ί : :Ois nerve iCSSS and/or right carotid body of said subject to modulate the neural activity of the left CSS and right CS« of the subject,

¾^■> , A method according to claim S3 when dependent on claim.28, wherein the signal applied to the left CKS or carotid body and the signal applied to the right CSS or carotid body is applied by the same neuromodula ion device.

SS.&. ffsethod according to claim S3 when dependent on claim 2B, wherein the signal applied to the left CSS or carotid foody and the signal applied to the right or carotid body is applied by different neuromodulatiors devices.

¾e . A ne omodulator electrical waveform for nee in treating nsulin resistance in « subjec , wherein the waveform is a kiicHerts alternating current (AC} waveform having a frequency of 1 co 50 SHr, such that, when applied to a carotid sinus nerve (CSM) of the subject, the &veforis inhibits neural signalling in he CSH, S^'?,¾ss of nearoffiodulation devi e for treating a condition associated with im aired glucose control in a subje t siwc a a insulin resistance, by modxtlatiog afferent ne ral activity in a carotid si axis ner e of the sub ect.

SS . A device,, isathod or use according to any prec ing claim, wnerain the subj ect is a. rsamrnal ian subject., optionally a huss&n subject..

;·.· ::· .··'·; device or method according to claim S3, where iK the sab-jeco is sxsifar ng frora a coriditiori, disease or disorder associated with, impaired glucose cont ol -